Drug delivery polymer and uses thereof

ABSTRACT

Described herein are platinum-based brush-arm star polymers (Pt-BASPs), or a pharmaceutical composition thereof, for delivery of platinum-based agents, such as cisplatin. Also provided are methods and kits involving the Pt-BASPs, or a pharmaceutical composition thereof, for treating proliferative diseases such as cancers (e.g., lung cancer, head-and-neck cancer, esophagus cancer, stomach cancer, breast cancer, pancreas cancer, liver cancer, kidney cancer, or prostate cancer) in a subject.

RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. §119(e) to U.S.provisional patent applications, U.S. Ser. No. 61/810,065, filed Apr. 9,2013, and U.S. Ser. No. 61/892,957, filed Oct. 18, 2013, each of whichis incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to polymers and macromolecules for the deliveryof therapeutic agents and methods of treating diseases.

BACKGROUND OF THE INVENTION

Platinum-based therapeutics form a cornerstone of treatment for solidtumor malignancies. Cisplatin is one of the most effectivechemotherapeutic agents against many forms of cancer includingtesticular, bladder, head and neck, ovarian, breast, lung, prostate, andrefractory non-Hodgkin's lymphomas (Jamieson et al., Chem Rev., 1999,99:2467-2498). Despite the ubiquitous use of cisplatin in oncology, thisdrug is associated with significant dose-limiting toxicities includingnephrotoxicity and neurotoxicity (Dhar et al., Proc. Nat. Acad. Sci.,2011, 1850-1855). Significant efforts have been devoted to developingnew strategies for safer and more effective platinum-based therapeuticstherapy.

Targeting controlled release polymer systems (e.g., targeted to aparticular tissue or cell type or targeted to a specific diseased tissuebut not normal tissue) is desirable because it reduces the amount of adrug present in tissues of the body that are not targeted. This isparticularly important when treating cancer where it is desirable that acytotoxic dose of the drug be delivered to cancer cells without killingthe surrounding non-cancerous tissue. Effective drug targeting canreduce the undesirable and sometimes life threatening side effectscommon with many anti-cancer therapies. Controlled release polymersystems can be designed to provide a drug level in the optimum rangeover a longer period of time, thus increasing the efficacy of the drugand minimizing problems with patient compliance.

SUMMARY OF THE INVENTION

Platinum-based agents play an important role in the treatment of cancer.Significant adverse reactions related to platinum-based agentsfrequently hinders the use of higher doses to achieve their maximumantineoplastic effects. The present invention provides platinum-basedbrush-arm star polymers (Pt-BASP) using “brush-first” ring-openingmetathesis polymerization (ROMP). The brush-first method involvessequential copolymerization of two functional monomers, a polymericmacromonomer followed by a multifunctional crosslinker, to generate aunimolecular micelle-like nanostructure with a core including thecrosslinker and a corona including the macromonomer (FIGS. 1A-1, 1A-2,and 1B). In certain embodiments, the Pt-BASPs described herein areuseful in the delivery and controlled release of platinum-based agents(e.g., platinum-based therapeutic agents). In certain embodiments, thePt-BASPs can be loaded with more than one therapeutic, diagnostic, orprophylactic agents in addition to the platinum-based agents (e.g.,platinum-based therapeutic agents) for multi-agent delivery). In certainembodiments, the platinum-based agent is cisplatin or a cisplatinderivative.

In one aspect, the present invention provides platinum complexes ofFormula (I):

and salts thereof. In certain embodiments, the platinum complexes ofFormula (I), and salts thereof, are prodrugs of a platinum-basedtherapeutic agent. In certain embodiments, the platinum complexes ofFormula (I), and salts thereof, are used as crosslinkers to preparePt-BASPs for the delivery of the platinum-based agents. In certainembodiments, a cisplatin-based platinum complex crosslinker isincorporated in BASPs. In certain embodiments, a cisplatin-basedplatinum complex crosslinker and a macromonomer containing a therapeuticagent are incorporated in the Pt-BASPs (see FIGS. 1A-1 and 1A-2).

In another aspect, the present invention provides methods of preparingplatinum complexes of Formula (I) and salts thereof. In certainembodiments, the platinum therapeutic agent is oxidized with an oxidantsuch as hydrogen peroxide, followed by treatment with a norborneneanhydride derivative.

In another aspect, the present invention provides a macromonomer ofFormula (III):

or a salt thereof. In certain embodiments, macromonomers of Formula(III) include a therapeutic, diagnostic, or prophylactic agent. Incertain embodiments, macromonomers of Formula (III) include one or moreanti-cancer agents. In certain embodiments, the anti-cancer agent is analkylating agent (e.g. nitrosoureas; procarbazine; dacarbazine;altretamine; and cisplatin). In certain embodiments, the anti-canceragent is an antimetabolite (e.g. methotrexate; purine antagonists suchas mercaptopurine (6-MP), thioguanine (6-TG), fludarabine phosphate,cladribine and pentostatin; pyrimidine antagonists such as fluorouracil(5-FU), cytarabine (ARA-C) and azacitidine; plant alkaloids such asvinblastine, vincristine, etoposide, teniposide, topotecan, irinotecan,paclitaxel and docetaxel). In certain embodiments, the anti-cancer agentis an antibiotic. In certain embodiments, the anti-cancer agent is ananthracycline, such as doxorubicin or daunorubicin; dactinomycin;idarubincin; plicamycin; mitomycin; or bleomycin. In certainembodiments, the anti-cancer agent is a hormonal agents (e.g. tamoxifen;flutamide; gonadotropin-releasing Hormone Agonistssuch as Leuprolide andGoserelin (Zoladex); aromatase Inhibitors such as aminoglutethimide andanastrozole. In certain embodiments, the anti-cancer agent is amsacrine;ydroxyurea; asparaginase; mitoxantrone; mitotane; retinoic acidderivatives; bone marrow growth factor; or amifostine. In certainembodiments, the anti-cancer agent is camptothecin or another member ofthe camptothecin family (e.g., topotecan or irinotecan). In certainembodiments, the anticancer agent is doxorubicin.

In another aspect, the present invention provides platinum-basedbrush-arm star polymers (Pt-BASP) using “brush-first” ring-openingmetathesis polymerization (ROMP). In certain embodiments, the Pt-BASPdescribed herein can be prepared by (a) reacting a macromonomer ofFormula (III) with a metathesis catalyst to form a polymerizationmixture; and (b) mixing the polymerization mixture from step (a) with asolution of a platinum complex of Formula (I). In certain embodiments,the polymer is a brush-arm star polymer (BASP) with the covalently boundplatinum-based agent as the core and poly(ethylene glycol) (PEG) as thecoronas (FIG. 1B). In certain embodiments, the macromonomer canintroduce one or more therapeutic, diagnostic, or prophylactic agents inaddition to the platinum-based agent (e.g., platinum-based therapeuticagent). In certain embodiments, the delivery of an agent (including aplatinum-based agent) included in a Pt-BASP described herein isratiometric. In certain embodiments, the delivery of each agent includedin a Pt-BASP described herein is ratiometric. In certain embodiments,the release of two or more agents (including a platinum-based agent)included in a Pt-BASP described herein from the Pt-BASP is orthogonal.In certain embodiments, the delivery of two or more agents (including aplatinum-based agent) included in a Pt-BASP described herein isorthogonal. In certain embodiments, the macromonomer introduces one ormore anti-cancer agents for combination delivery. In certainembodiments, the provided Pt-BASPs are loaded with more than onetherapeutic, diagnostic, or prophylactic agents and can be prepared by(a) reacting a macromonomer of Formula (III) having one therapeutic,diagnostic, or prophylactic agent, with another macromonomer of Formula(III) having a different therapeutic, diagnostic, or prophylactic agent,in the presence of a metathesis catalyst to form a polymerizationmixture; and (b) mixing the polymerization mixture from step (a) with asolution of a platinum complex of Formula (I). In certain embodiments,the Pt-BASPs as described herein are loaded with cisplatin, camptothecinand doxorubicin (see FIG. 10). In certain embodiments, the Pt-BASPsloaded with cisplatin, camptothecin, and doxorubicin are prepared by (a)reacting a doxorubicin-loaded macromonomer of Formula (III) with acamptothecin-loaded macromonomer of Formula (III) in the presence of ametathesis catalyst to form a polymerization mixture; and (b) mixing thepolymerization mixture from step (a) with a solution of a platinumcomplex of Formula (I).

In another aspect, the present invention provides pharmaceuticalcompositions comprising a polymer described herein and apharmaceutically acceptable excipient. In certain embodiments, a polymerdescribed herein is provided as a polymeric nanoparticle. The size ofthe polymeric nanoparticle may be determined by the molar ratio of allthe macromonomers to the crosslinker employed in a method of preparingthe polymeric nanoparticle (e.g., Method A or B). In certainembodiments, the polymeric nanoparticle is of radius size about 1 nm toabout 1000 nm. In certain embodiments, the polymeric nanoparticle is ofradius size about 1 nm to about 200 nm. In certain embodiments, thepolymeric nanoparticle is of radius size about 1 nm to about 20 nm. Incertain embodiments, the polymeric nanoparticle is of radius size about1 nm to about 10 nm. In certain embodiments, the pharmaceuticalcompositions described herein include a therapeutically effective amountof a polymer described herein. The pharmaceutical composition may beuseful for treating a proliferative disease such as cancer.

In another aspect, the present invention provides methods for treatingproliferative diseases. Exemplary proliferative diseases include cancers(e.g., leukemia, melanoma, multiple myeloma, solid tumors), benignneoplasms, angiogenesis, angiogenesis-associated diseases, inflammatorydiseases, autoinflammatory diseases, and autoimmune diseases.

In another aspect, the present invention provides kits comprising aplatinum complex of Formula (I) and/or a polymer described herein. Thekits of the invention may include a single dose or multiple doses of aplatinum complex of Formula (I) and/or a polymer described herein. Theprovided kits may be useful for the treatment of proliferative diseasessuch as cancers. In certain embodiments, the kits described hereinfurther include instructions for administering the platinum complex ofFormula (I) and/or a polymer described herein. The kits may also includepackaging information describing the use or prescribing information forthe subject or a health care professional. Such information may berequired by a regulatory agency such as the U.S. Food and DrugAdministration (FDA). The kit may also optionally include a device foradministration of the compound or composition, for example, a syringefor parenteral administration.

The details of certain embodiments of the invention are set forthherein. Other features, objects, and advantages of the invention will beapparent from the Detailed Description, Figures, Examples, and Claims.

DEFINITIONS Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer.Isomers can be isolated from mixtures by methods known to those skilledin the art, including chiral high pressure liquid chromatography (HPLC)and the formation and crystallization of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY,1962); and Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972). The invention additionally encompasses compounds asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), n-propyl(C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl(C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆).Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈)and the like. Unless otherwise specified, each instance of an alkylgroup is independently unsubstituted (an “unsubstituted alkyl”) orsubstituted (a “substituted alkyl”) with one or more substituents. Incertain embodiments, the alkyl group is an unsubstituted C₁₋₁₀ alkyl(e.g., —CH₃). In certain embodiments, the alkyl group is a substitutedC₁₋₁₀ alkyl.

The term “heteroalkyl” refers to an alkyl group which further includesat least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected fromoxygen, nitrogen, or sulfur within (i.e., inserted between adjacentcarbon atoms of) and/or placed at one or more terminal position(s) ofthe parent chain. In certain embodiments, a heteroalkyl group refers toa saturated group having from 1 to 10 carbon atoms and 1 or moreheteroatoms within the parent chain (“heteroC₁₋₁₀ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₉ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 8 carbon atoms and 1 or more heteroatomswithin the parent chain (“heteroC₁₋₈ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1or more heteroatoms within the parent chain (“heteroC₁₋₇ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 6carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₆ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms withinthe parent chain (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC₁₋₄ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 3carbon atoms and 1 heteroatom within the parent chain (“heteroC₁₋₃alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 2 carbon atoms and 1 heteroatom within the parent chain(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parentchain (“heteroC₂₋₆ alkyl”). Unless otherwise specified, each instance ofa heteroalkyl group is independently unsubstituted (an “unsubstitutedheteroalkyl”) or substituted (a “substituted heteroalkyl”) with one ormore substituents. In certain embodiments, the heteroalkyl group is anunsubstituted heteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkylgroup is a substituted heteroC₁₋₁₀ alkyl.

The term “alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In someembodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂₋₉ alkenyl”).In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms(“C₂₋₇ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently unsubstituted (an “unsubstitutedalkenyl”) or substituted (a “substituted alkenyl”) with one or moresubstituents. In certain embodiments, the alkenyl group is anunsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl groupis a substituted C₂₋₁₀ alkenyl.

The term “alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently unsubstituted (an “unsubstitutedalkynyl”) or substituted (a “substituted alkynyl”) with one or moresubstituents. In certain embodiments, the alkynyl group is anunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₁₀ alkynyl.

The term “carbocyclyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbonatoms (“C₃₋₁₀ carbocyclyl”) and zero heteroatoms in the non-aromaticring system. In some embodiments, a carbocyclyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 7 ring carbon atoms (“C₃₋₇ carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ringcarbon atoms (“C₄₋₆ carbocyclyl”). In some embodiments, a carbocyclylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include, withoutlimitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄),cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl(C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. ExemplaryC₃₋₈ carbocyclyl groups include, without limitation, the aforementionedC₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈),cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl(C₈), and the like. Exemplary C₃₋₁₀ carbocyclyl groups include, withoutlimitation, the aforementioned C₃₋₈ carbocyclyl groups as well ascyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl(C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀),spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can besaturated or can contain one or more carbon-carbon double or triplebonds. “Carbocyclyl” also includes ring systems wherein the carbocyclylring, as defined above, is fused with one or more aryl or heteroarylgroups wherein the point of attachment is on the carbocyclyl ring, andin such instances, the number of carbons continue to designate thenumber of carbons in the carbocyclic ring system. Unless otherwisespecified, each instance of a carbocyclyl group is independentlyunsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is an unsubstituted C₃₋₁₀carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃₋₁₀ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C₄₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ringcarbon atoms (“C₅₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 10 ring carbon atoms (“C₅₋₁₀ cycloalkyl”). Examples ofC₅₋₆ cycloalkyl groups include cyclopentyl (C₅) and cyclohexyl (C₅).Examples of C₃₋₆ cycloalkyl groups include the aforementioned C₅₋₆cycloalkyl groups as well as cyclopropyl (C₃) and cyclobutyl (C₄).Examples of C₃₋₈ cycloalkyl groups include the aforementioned C₃₋₆cycloalkyl groups as well as cycloheptyl (C₇) and cyclooctyl (C₈).Unless otherwise specified, each instance of a cycloalkyl group isindependently unsubstituted (an “unsubstituted cycloalkyl”) orsubstituted (a “substituted cycloalkyl”) with one or more substituents.In certain embodiments, the cycloalkyl group is an unsubstituted C₃₋₁₀cycloalkyl. In certain embodiments, the cycloalkyl group is asubstituted C₃₋₁₀ cycloalkyl.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to14-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or polycyclic (e.g., a fused, bridged or spiro ring system such as abicyclic system (“bicyclic heterocyclyl”) or tricyclic system(“tricyclic heterocyclyl”)), and can be saturated or can contain one ormore carbon-carbon double or triple bonds. Heterocyclyl polycyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.In certain embodiments, the heterocyclyl group is a substituted 3-14membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining 2 heteroatoms include, without limitation, dioxolanyl,oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groupscontaining 3 heteroatoms include, without limitation, triazolinyl,oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclylgroups containing 1 heteroatom include, without limitation, piperidinyl,tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-memberedheterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary6-membered heterocyclyl groups containing 3 heteroatoms include, withoutlimitation, triazinanyl. Exemplary 7-membered heterocyclyl groupscontaining 1 heteroatom include, without limitation, azepanyl, oxepanyl,and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or14 it electrons shared in a cyclic array) having 6-14 ring carbon atomsand zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. Unless otherwise specified, each instance of an aryl group isindependently unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certainembodiments, the aryl group is an unsubstituted C₆₋₁₄ aryl. In certainembodiments, the aryl group is a substituted C₆₋₁₄ aryl.

The term “heteroaryl” refers to a radical of a 5-14 membered monocyclicor polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system(e.g., having 6, 10, or 14π electrons shared in a cyclic array) havingring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen and sulfur (“5-14 membered heteroaryl”). In heteroaryl groupsthat contain one or more nitrogen atoms, the point of attachment can bea carbon or nitrogen atom, as valency permits. Heteroaryl polycyclicring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the point of attachment is on the heteroaryl ring, and insuch instances, the number of ring members continue to designate thenumber of ring members in the heteroaryl ring system. “Heteroaryl” alsoincludes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more aryl groups wherein the point of attachment iseither on the aryl or heteroaryl ring, and in such instances, the numberof ring members designates the number of ring members in the fusedpolycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groupswherein one ring does not contain a heteroatom (e.g., indolyl,quinolinyl, carbazolyl, and the like) the point of attachment can be oneither ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted 5-14membered heteroaryl. In certain embodiments, the heteroaryl group is asubstituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include,without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary5-membered heteroaryl groups containing 2 heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing 3heteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4heteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing 1 heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, andpyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing 1heteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplarytricyclic heteroaryl groups include, without limitation,phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl,phenoxazinyl and phenazinyl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by a heteroaryl group, wherein the point of attachment is onthe alkyl moiety.

Affixing the suffix “-ene” to a group indicates the group is a divalentmoiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene isthe divalent moiety of alkenyl, alkynylene is the divalent moiety ofalkynyl, heteroalkylene is the divalent moiety of heteroalkyl,heteroalkenylene is the divalent moiety of heteroalkenyl,heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclyleneis the divalent moiety of carbocyclyl, heterocyclylene is the divalentmoiety of heterocyclyl, arylene is the divalent moiety of aryl, andheteroarylene is the divalent moiety of heteroaryl.

As understood from the above, alkyl, alkenyl, alkynyl, carbocyclyl,aryl, and heteroaryl groups are, in certain embodiments, optionallysubstituted. Optionally substituted refers to a group which may besubstituted or unsubstituted (e.g., “substituted” or “unsubstituted”alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or“unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl,“substituted” or “unsubstituted” heterocyclyl, “substituted” or“unsubstituted” aryl or “substituted” or “unsubstituted” heteroarylgroup). In general, the term “substituted” means that at least onehydrogen present on a group is replaced with a permissible substituent,e.g., a substituent which upon substitution results in a stablecompound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with allpermissible substituents of organic compounds, any of the substituentsdescribed herein that results in the formation of a stable compound. Thepresent invention contemplates any and all such combinations in order toarrive at a stable compound. For purposes of this invention, heteroatomssuch as nitrogen may have hydrogen substituents and/or any suitablesubstituent as described herein which satisfy the valencies of theheteroatoms and results in the formation of a stable moiety.

The term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine(chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

The term “hydroxyl” or “hydroxy” refers to the group —OH. The term“substituted hydroxyl” or “substituted hydroxyl,” by extension, refersto a hydroxyl group wherein the oxygen atom directly attached to theparent molecule is substituted with a group other than hydrogen, andincludes groups selected from —OR^(aa), —ON(R^(bb))₂, —OC(═O)SR^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa),—OSO₂R^(aa), —OSi(R^(aa))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. In the case wherein “substituted hydroxyl” is a ligand L₁ or L₂,“substituted hydroxyl” also refers to the group (R^(aa))₂O, whereinR^(aa) is as defined herein.

The term “thiol” or “thio” refers to the group —SH. The term“substituted thiol” or “substituted thio,” by extension, refers to athiol group wherein the sulfur atom directly attached to the parentmolecule is substituted with a group other than hydrogen, and includesgroups selected from —SR^(aa), —S═SR^(cc), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —SC(═O)OR^(aa), and —SC(═O)R^(aa), wherein R^(aa) andR^(cc) are as defined herein.

The term, “amino” refers to the group —NH₂.

The term “monosubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule, or coordinatedto an iron atom, is substituted with one hydrogen and one group otherthan hydrogen, and includes groups selected from —NH(R^(bb)),—NHC(═O)R^(aa), —NHCO₂R^(aa), —NHC(═O)N(R^(bb))₂,—NHC(═NR^(bb))N(R^(bb))₂, —NHSO₂R^(aa), —NHP(═O)(OR^(cc))₂, and—NHP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb) and R^(cc) are as definedherein, and wherein R^(bb) of the group —NH(R^(bb)) is not hydrogen.

The term “disubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule, or coordinatedto an iron atom, is substituted with two groups other than hydrogen, andincludes groups selected from —N(R^(bb))₂, —NR^(bb) C(═O)R^(aa),—NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂, —NR^(bb)C(═NR^(bb))₂,—NR^(bb)SO₂R^(aa), —NR^(bb)P(═O)(OR^(cc))₂, and —NR^(bb)P(═O)(NR^(bb))₂,wherein R^(aa), R^(bb), and R^(cc) are as defined herein, with theproviso that the nitrogen atom directly attached to the parent moleculeis not substituted with hydrogen.

The term “trisubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule, or coordinatedto an iron atom, is substituted with three groups, and includes groupsselected from —N(R^(bb))₃ and —N(R^(bb))₃ ⁺X⁻, wherein R^(bb) and X⁻ areas defined herein.

In certain embodiments, the substituent present on the nitrogen atom isan nitrogen protecting group (also referred to herein as an “aminoprotecting group”). Nitrogen protecting groups include, but are notlimited to, —OH, —OR, —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀heteroalkyl, C₂₋₁₀ heteroalkenyl, C₂₋₁₀ heteroalkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined herein. Nitrogen protecting groups are well known in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamante, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa),—CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate(BOC), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzylcarbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththylcarbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on an sulfur atom is asulfur protecting group (also referred to as a “thiol protectinggroup”). Sulfur protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Sulfur protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and Claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

The use of the phrase “at least one instance” refers to 1, 2, 3, 4, ormore instances, but also encompasses a range, e.g., for example, from 1to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4instances, inclusive.

Other Definitions

The following definitions are more general terms used throughout thepresent application:

The term “salt” refers to ionic compounds that result from theneutralization reaction of an acid and a base. A salt is composed of oneor more cations (positively charged ions) and one or more anions(negative ions) so that the salt is electrically neutral (without a netcharge). Salts of the compounds of this invention include those derivedfrom inorganic and organic acids and bases. Examples of acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, andperchloric acid, or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid, or malonic acidor by using other methods known in the art such as ion exchange. Othersalts include adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further salts include ammonium,quaternary ammonium, and amine cations formed using counterions such ashalide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and aryl sulfonate.

A “polymer” is given its ordinary meaning as used in the art, i.e., amolecular structure comprising one or more repeat units (monomers),connected by covalent bonds. The repeat units may all be identical, orin some cases, there may be more than one type of repeat unit presentwithin the polymer. In certain embodiments, the polymer has C═C. Incertain embodiments, the polymer is prepared from ring openingmetathesis polymerization.

The term “cross-linker” refers to compounds that link one polymer chainto another by covalent bonds or ionic bonds. “Polymer chains” can referto synthetic polymers or natural polymers (such as proteins).

The term “macromonomer” refers to a macromolecule with one end-groupthat enables it to act as a monomer. Macromonomers will contribute asingle monomeric unit to a chain of the completed macromolecule.

The term “prodrugs” refer to compounds and/or polymers, includingcompounds of Formula (I) and polymers of Formula (III), which havecleavable groups and become active by solvolysis, reduction, oxidation,or under physiological conditions, to provide the pharmaceuticallyactive compounds in vivo. Prodrugs include polymeric derivativesconjugated with the pharmaceutical active compounds known topractitioners of the art, such as, for example, to form an ester byreaction of the acid, or acid anhydride, or mixed anhydrides moieties ofthe polymer of the polymer with the hydroxyl moiety of thepharmaceutical active compound, or to form an amide prepared by theacid, or acid anhydride, or mixed anhydrides moieties of the polymerwith a substituted or unsubstituted amine of the pharmaceutically activecompound. Simple aliphatic or aromatic esters, amides, and anhydridesderived from acidic groups pendant on the polymers of this invention areparticular prodrugs. In some embodiments, the polymer incorporates onetherapeutic agent. In some embodiments, the polymer incorporates morethan one therapeutic agents.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult, or senior adult)) and/or othernon-human animals, for example, mammals (e.g., primates (e.g.,cynomolgus monkeys, rhesus monkeys); commercially relevant mammals suchas cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds(e.g., commercially relevant birds such as chickens, ducks, geese,and/or turkeys). In certain embodiments, the animal is a mammal. Theanimal may be a male or female and at any stage of development. Anon-human animal may be a transgenic or genetically engineered animal.

The terms “administer,” “administering,” or “administration” refer toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing an inventive polymer, or a pharmaceutical compositionthereof, or a device incorporating the inventive polymer.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of a“pathological condition” (e.g., a disease, disorder, or condition, orone or more signs or symptoms thereof) described herein. In someembodiments, treatment may be administered after one or more signs orsymptoms have developed or have been observed. In other embodiments,treatment may be administered in the absence of signs or symptoms of thedisease or condition. For example, treatment may be administered to asusceptible individual prior to the onset of symptoms (e.g., in light ofa history of symptoms and/or in light of genetic or other susceptibilityfactors). Treatment may also be continued after symptoms have resolved,for example, to delay or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of refers to an amount sufficient to elicit adesired biological response, i.e., treating the condition. As will beappreciated by those of ordinary skill in this art, the effective amountof an inventive polymer may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thecondition being treated, the mode of administration, and the age andhealth of the subject. An effective amount encompasses therapeutic andprophylactic treatment. For example, in treating cancer, an effectiveamount of an inventive compound may reduce the tumor burden or stop thegrowth or spread of a tumor. In treating macular degeneration, aneffective amount of an inventive compound may improve sight, reduce therisk of vision loss, or prevent central vision loss from worsening.

A “therapeutically effective amount” is an amount sufficient to providea therapeutic benefit in the treatment of a condition or to delay orminimize one or more symptoms associated with the condition. Atherapeutically effective amount of an inventive polymer means an amountof therapeutic agent, alone or in combination with other therapies,which provides a therapeutic benefit in the treatment of the condition.The term “therapeutically effective amount” can encompass an amount thatimproves overall therapy, reduces or avoids symptoms or causes of thecondition, or enhances the therapeutic efficacy of another therapeuticagent.

A “prophylactically effective amount” is an amount sufficient to preventa condition, or one or more symptoms associated with the condition orprevent its recurrence. A prophylactically effective amount of acompound means an amount of a therapeutic agent, alone or in combinationwith other agents, which provides a prophylactic benefit in theprevention of the condition. The term “prophylactically effectiveamount” can encompass an amount that improves overall prophylaxis orenhances the prophylactic efficacy of another prophylactic agent.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis or diseases associated withangiogenesis, inflammatory diseases, autoinflammatory diseases, andautoimmune diseases.

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated with the growth of a normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An example of a pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites.

The term “metastasis,” “metastatic,” or “metastasize” refers to thespread or migration of cancerous cells from a primary or original tumorto another organ or tissue and is typically identifiable by the presenceof a “secondary tumor” or “secondary cell mass” of the tissue type ofthe primary or original tumor and not of that of the organ or tissue inwhich the secondary (metastatic) tumor is located. For example, aprostate cancer that has migrated to bone is said to be metastasizedprostate cancer and includes cancerous prostate cancer cells growing inbone tissue.

The term “cancer” refers to a malignant neoplasm (Stedman's MedicalDictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia,1990). Exemplary cancers include, but are not limited to, acousticneuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma(e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma);appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g.,cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinomaof the breast, papillary carcinoma of the breast, mammary cancer,medullary carcinoma of the breast); brain cancer (e.g., meningioma,glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma),medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer(e.g., cervical adenocarcinoma); choriocarcinoma; chordoma;craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer,colorectal adenocarcinoma); connective tissue cancer; epithelialcarcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma,multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g.,uterine cancer, uterine sarcoma); esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing'ssarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma);familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germcell cancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL),acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomasuch as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) andnon-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large celllymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., Waldenstrim's macroglobulinemia), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma), heavy chain disease (e.g., alphachain disease, gamma chain disease, mu chain disease); hemangioblastoma;hypopharynx cancer; inflammatory myofibroblastic tumors; immunocyticamyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor,renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC),malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, smallcell lung cancer (SCLC), non-small cell lung cancer (NSCLC),adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g.,systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS);mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera(PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM)a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronicmyelocytic leukemia (CML), chronic neutrophilic leukemia (CNL),hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g.,neurofibromatosis (NF) type 1 or type 2, schwannomatosis);neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor(GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovariancancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarianadenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g.,pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm(IPMN), Islet cell tumors); penile cancer (e.g., Paget's disease of thepenis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT);plasma cell neoplasia; paraneoplastic syndromes; intraepithelialneoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectalcancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g.,squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basalcell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); softtissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma,malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma,fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestinecancer; sweat gland carcinoma; synovioma; testicular cancer (e.g.,seminoma, testicular embryonal carcinoma); thyroid cancer (e.g.,papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC),medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvarcancer (e.g., Paget's disease of the vulva).

The term “angiogenesis” refers to the formation and growth of new bloodvessels. Normal angiogenesis occurs in the body of a healthy subjectduring wound healing and for restoring blood flow to tissues afterinjury. The body controls angiogenesis through a number of means, e.g.,angiogenesis-stimulating growth factors and angiogenesis inhibitors.Many disease states, such as cancer, diabetic blindness, age-relatedmacular degeneration, rheumatoid arthritis, and psoriasis, arecharacterized by abnormal (i.e., increased or excessive) angiogenesis.Abnormal angiogenesis refers to angiogenesis greater than that in anormal body, especially angiogenesis in an adult not related to normalangiogenesis (e.g., menstruation or wound healing). Abnormalangiogenesis can result in new blood vessels that feed diseased tissuesand/or destroy normal tissues, and in the case of cancer, the newvessels can allow tumor cells to escape into the circulation and lodgein other organs (tumor metastases).

The term “ratiometric” refers to the situation where C₁ ^(i) issubstantially equal to C₀ ^(i), wherein C₀ ^(i) refers to the ratio ofthe amount of a first agent before the first agent is delivered to asubject, tissue, or cell, to the total amount of two or more agents(including the first agent) before the two or more agents are deliveredto the subject, tissue, or cell; and C₁ ^(i) refers to the ratio of theamount of the first agent that is delivered to the subject, tissue, orcell, to the total amount of the two or more agents (including the firstagent) that are delivered to the subject, tissue, or cell. In certainembodiments, the delivery of each one of the two or more agents isratiometric.

The term “orthogonal” refers to the situation where a first agent and asecond agent, each of which is included in a Pt-BASP described herein,is independently released from the Pt-BASP. In certain embodiments,under condition A, the first agent, but not the second agent, isreleased from the Pt-BASP. For example, an orthogonal release ororthogonal delivery of the first and second agents includes: undercondition A, the first agent, but not the second agent, is released fromthe Pt-BASP; under condition B, the second agent, but not the firstagent, is released from the Pt-BASP. The release or delivery of thefirst and second agents is not orthogonal when, for example, undercondition C, both the first and second agents are released from thePt-BASP.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1 and 1A-2 show an exemplary synthesis of Pt-BASPs loaded withmore than one therapeutic agents.

FIG. 1B shows an exemplary synthesis of the cisplatin prodrugcrosslinker XL3.

FIG. 2 shows an exemplary synthesis of platinum brush-arm star polymers(Pt-BASPs) with cisplatin prodrug crosslinker XL3. PEG-basedmacromonomer (MM) 4 (m equiv.) is first exposed to 1.0 equiv. ofcatalyst C-1 (cat.) in tetrahydrofuran for 10 min to generate livingbottle-brush polymer initiators (BIs). Transfer of the BI solution tosolid XL3 initiates crosslinking and formation of Pt-BASPs with densePt-loaded cores and PEG coronas. Upon reduction, cleavage of the O—Ptbonds from XL3 leads to simultaneous Pt-BASP degradation and release ofthe platinum-based therapeutic agent such as cisplatin.

FIG. 3A shows gel permeation chromatography (GPC) evaluation of themolecular weight of exemplary cisplatin-based Pt-BASPs. Theweight-average molecular weights (MWs) and dispersity indices (

) of each Pt-BASP (specific samples referred to by their m and N values,e.g., m5N3) were obtained by gel permeation chromatography (GPC) coupledwith a multi-angle laser light scattering (MALLS) detector using DMFwith 0.2 M LiBr eluent. The molecular weight generally increases with Nand decreases with m; these trends agree with our previously proposedgrowth mechanism. The GPC traces were monomodal and the

values were low (<1.3) for most m and N combinations. The averagenumbers of BIs per Pt-BASP (<#BI>) and platinum atoms per Pt-BASP(<#Pt>), and the corresponding weight percentage of cisplatin (% 1), arelisted in Table 1 as shown in FIG. 4. From this series of parallelreactions a range of cisplatin loadings from 1% to 9% was achieved.Increasing N or truncating compound 4 could increase these values.

FIG. 3B shows images of exemplary cisplatin-based Pt-BASPs particlesfrom transmission electron microscopy (TEM). TEM of unstained Pt-BASPsrevealed particles that ranged from 2.0 nm to 5.0 nm in diameter. Theobserved particle sizes correspond to the core size D_(core) (see FIG.4). D_(core) generally increased with percentage of cisplatin 1. Largerparticles were observed when samples were stained with RuO₄ prior toimaging. For example, the m5N5 sample, which had an unstained size of3.3±0.5 nm, possessed a stained size of 9.3±0.9. This can be attributedto RuO₄ staining at least a portion of the PEG corona.

FIG. 3C shows histograms of hydrodynamic radii (R_(H)) of exemplarycisplatin-based Pt-BASPs.

FIG. 4 shows Table 1 of characterization data for Pt-BASPs. Thehydrodynamic diameters (D_(H)) of each Pt-BASP were measured by dynamiclight scattering (DLS). Values for D_(H) ranged from 11.0±0.4 nm to16.0±0.2 nm, and generally increased with MW (Table 1). Since D_(H)captures the size of the Pt-BASP plus its hydrated shell, D_(H) valuescan be larger than the diameters measured by TEM. In the case of them5N5 sample, the D_(H) value is of 11.6±0.3 and the TEM value is9.3±0.9.

FIGS. 3-4 demonstrate that the Pt-BASP sizes and Pt loadings can betuned by adjusting m and N. Increasing m (BI length) generally increasessteric bulk and limits the extent of crosslinking; shorter BIs (smallerm) generally lead to larger Pt-BASPs. Increasing N (Pt loading)generally directly increases the core size and reduces steric hindrance,which leads to increased <#BI>.

FIG. 5A shows GPC traces before and after exemplary cisplatin-basedPt-BASPs degradation in the presence of glutathione (GSH). Exposure of aPt-BASP (m5N5) sample to excess glutathione (GSH) reducing agent indeionized water led to complete degradation of the Pt-BASP as confirmedby GPC.

FIG. 5B shows release kinetics curve of exemplary cisplatin carried bym5N5 sample. Two sets of conditions were explored: first, the Pt-BASPwas dialyzed against 100 mL of PBS at pH 7.4 and 37° C.; second, thePt-BASP was dialyzed against 100 mL of 10 mM GSH in PBS at pH 7.4 and37° C. The former conditions mimic extracellular media, whereas thelatter mimic the reducing intracellular environment. The Pt content fromsamples of the solution outside the dialysis membrane was obtained byinductively coupled plasma atomic emission spectroscopy (ICP-AES). Datafor % Pt released versus time are shown in FIG. 5B. Under both sets ofconditions, extended release of Pt was observed over the course of 10 d.In the presence of GSH the % Pt released was 50% after 5 d, and reached60% after 10 d. In the absence of GSH, the % Pt released was 30% after10 d. The presence of GSH led to a significant burst release over thefirst 2 d followed by an extended period of linear release. Theseresults indicate that Pt-BASPs may be useful architectures for triggeredintracellular release of cisplatin. From the release kineticsexperiment, only a fraction (˜39% for the GSH sample) of the cisplatincarried by m5N5 is released within 48 h.

FIG. 5C shows HeLa cell viability in the presence of m5N5 and freecisplatin (compound 1) as quantified by MTT assay. The cells wereexposed to solutions of Pt-BASP or free cisplatin with varied total Ptconcentration for 48 hours. As shown in FIG. 5C, the Pt-BASP (squares)had an IC₅₀=37 μM; cisplatin (circles) had an IC₅₀=23 μM. The samekinetics for the cell culture experiment is assumed, then thedose-response curve for the Pt-BASP is shifted to lower concentration togive an IC₅₀=14 μM (triangles, m5N5*, star suggests identifying adifferent curve (the curve shifted to lower IC50)). The observation thatPt-BASPs display similar IC₅₀ values to cisplatin, but only 18-39% ofthe Pt is released, suggesting that at least a fraction of the Pt-BASPmaterial is internalized. Addition of ligands to the PEG periphery thatinduce internalization may lead to even greater efficacy.

FIG. 6 shows the toxicity of exemplary Pt-BASPs against Hela cells. Thevarious Pt-BASPs carry either Pt alone, Pt and camptothecin (CPT), or PTand CPT and doxorubicin (DOX). The DOX is connected to Pt-BASPs by aphotocleavable linker. When the Pt-BASP is irradiated with light, DOX isreleased, and the IC₅₀ is shifted to a lower value. These Pt-BASPparticles are capable of releasing 3 different chemotherapeutic agentsfor combination therapy.

FIG. 7 shows an exemplary camptothecin-loaded macromonomer (CPT-MM) anddoxorubicin-loaded macromonomer (Dox-MM).

FIG. 8A shows release of camptothecin from a camptothecin-loadedmacromonomer. FIG. 8B shows release of doxorubicin from adoxorubicin-loaded macromonomer.

FIG. 9A shows Brush-First synthesis of nanoparticles from adoxorubicin-loaded macromonomer (Dox-MM). FIG. 9B shows use of anexemplary platinum-based crosslinker in the Brush-First synthesis ofnanoparticles.

FIG. 10 shows synthesis of exemplary multi-drug loaded nanoparticles,3CPT-4DOX-3Pt, using “brush-first” ring-opening metathesispolymerization (ROMP). The exemplary nanoparticles are prepared from 3equivalents of CPT-MM (see FIG. 7), 4 equivalents of Dox-MM (see FIG.7), and 3 equivalents of the platinum-based cross-linker (see FIG. 9B).

FIG. 11 shows characterization of the exemplary multi-drug loadednanoparticle 3CPT-4DOX-3Pt.

FIG. 12 shows the Pt-release from the exemplary multi-drug loadednanoparticle 3CPT-4DOX-3Pt.

FIG. 13 shows UV-absorbance changes over 1 min, 3 min, 6 min, 10 min, 15min, and 20 min during the drug release from the exemplary multi-drugloaded nanoparticle 3CPT-4DOX-3Pt.

FIG. 14A shows in vitro cytotoxicity of the exemplary multi-drug loadednanoparticle 3CPT-4DOX-3Pt against Hela cells. FIG. 14B shows exemplaryinternalization results of 3CPT-4DOX-3Pt into Hela cells. DAPI:4′,6-diamidino-2-phenylindole.

FIG. 15A shows the chemical structures exemplary macromonomers. FIG. 15Bshows an exemplary synthesis of polymer P3 (3-drug BASP). Orthogonaldrug release occurs in response to three distinct triggers (e.g., H₃O⁺(hydrolysis), hv (UV irradiation), and redox. (reduction)). Pt:cisplatin.

FIG. 16 shows exemplary gel permeation chromatography (GPC) traces ofexemplary Pt-BASPs. P0 is a non-agent-loaded (e.g., non-drug-loaded)BASP, which is shown in FIG. 27. Ctrl is a parent brush polymer with nocrosslinker (e.g., XL3) added and is not a BASP. Residual macromonomeris indicated with a star.

FIG. 17 shows exemplary dynamic light scattering (DLS) histograms forpolymers P1, P2a, P2b, and P3.

FIG. 18 shows exemplary transmission electron microscopy (TEM) images ofpolymer P3. Scale bar corresponds to 100 nm.

FIG. 19 shows exemplary TEM images of the unstained Pt-BASPs in the drystate (cast from aqueous solution).

FIG. 20 shows exemplary Cryo TEM images of polymers P1, P2a, P2b, and P3in aqueous solution. P0: non-drug loaded BASP (FIG. 27). The scale baris 100 nm.

FIG. 21A shows exemplary OVCAR3 cell viability data after 72 h oftreatment with 5% glucose (0) and polymers P1, P2a, P2b, and P3. Datalabeled “+hv” were obtained from cells treated with polymer P1, P2a,P2b, or P3, irradiated with 365 nm light for 10 min, and then incubatedfor a total of 72 h. Solid and dashed lines represent sigmoidal fits fordark and irradiated samples, respectively. FIG. 21B is a bar chartshowing exemplary IC₅₀ values of polymers P1, P2a, P2b, and P3 alongwith statistical comparisons. Error represents SEM of four technicalreplicates.

FIG. 22 shows exemplary OVCAR3 cell viability data after 72 h oftreatment with P0, a non-agent-loaded BASP (FIG. 27).

FIG. 23 shows exemplary photo-triggered release of DOX in OVCAR3 cellsas monitored by live-cell confocal fluorescence imaging. Cells wereloaded with polymer P2b for 30 min and concurrently exposed to 405 nm UVirradiation during imaging of doxorubicin (red or light grey;λ_(ex)/λ_(em)=561/595 nm) and nuclei (acridine orange, green or darkgrey; λ_(ex)/λ_(em)=488/525 nm). Scale bar is 5 μm.

FIG. 24 shows the mean DOX fluorescence intensity (fold versus time 0)of polymer P2b as a function of irradiation time (seconds).

FIG. 25 shows an exemplary ¹H NMR spectrum of DOX-MM in CD₂Cl₂.

FIG. 26 shows an exemplary ¹H NMR spectrum of CPT-MM in CD₂Cl₂.

FIG. 27 shows the chemical structure of P0, a non-agent-loaded BASP.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

Platinum-based agents are widely used in cancer chemotherapy.Significant adverse reactions related to platinum-based agentsfrequently hinder the use of higher doses to achieve their maximumantineoplastic effects. The present invention provides platinum-basedbrush-arm star polymers (Pt-BASPs) and methods for the controlleddelivery of platinum-based therapeutic agents. In certain embodiments,the Pt-BASPs are loaded with more than one therapeutic, diagnostic, orprophylactic agents in addition to the platinum-based therapeutic agentsfor multi-agent delivery.

Platinum Complex Crosslinkers

In one aspect, the present invention provides a platinum complex ofFormula (I):

or a salt thereof,wherein:

X₁ is F, Cl, Br, or I;

X₂ is F, Cl, Br, or I;

each instance of R^(N1) and R^(N2) is independently hydrogen, optionallysubstituted C₁₋₆ alkyl, or a nitrogen protecting group; or two R^(N1)are taken with the intervening atoms to form a heterocyclic ring; or twoR^(N2) are taken with the intervening atoms to form a heterocyclic ring;or R^(N1) and R^(N2) are taken with the intervening atoms to form aheterocyclic ring; and n is 1, 2, 3, 4, 5, or 6.

As generally defined herein, X₁ is F, Cl, Br, or I. In certainembodiments, X₁ is F. In certain embodiments, X₁ is Cl. In certainembodiments, X₁ is Br. In certain embodiments, X₁ is I.

As generally defined herein, X₂ is F, Cl, Br, or I. In certainembodiments, X₂ is F. In certain embodiments, X₂ is Cl. In certainembodiments, X₂ is Br. In certain embodiments, X₂ is I.

In certain embodiments, X₁ and X₂ are the same. In certain embodiments,X₁ and X₂ are F. In certain embodiments, X₁ and X₂ are Cl. In certainembodiments, X₁ and X₂ are Br. In certain embodiments, X₁ and X₂ are I.In certain embodiments, X₁ and X₂ are different. In certain embodiments,X₁ is Cl, and X₂ is F. In certain embodiments, X₁ is Cl, and X₂ is Br.In certain embodiments, X₁ is Cl, and X₂ is I. In certain embodiments,X₁ is Br, and X₂ is I. In certain embodiments, X₁ is F, and X₂ is I. Incertain embodiments, X₁ is F, and X₂ is Br.

As generally defined herein, each instance of R^(N1) is independentlyhydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogen protectinggroup, or two R^(N1) are taken with the intervening atoms to form aheterocyclic ring. In certain embodiments, R^(N1) is nitrogen. Incertain embodiments, R^(N1) is optionally substituted C₁₋₆ alkyl. Incertain embodiments, R^(N1) is substituted C₁₋₆ alkyl. In certainembodiments, R^(N1) is unsubstituted C₁₋₆ alkyl. In certain embodiments,R^(N1) is methyl. In certain embodiments, R^(N1) is ethyl. In certainembodiments, R^(N1) is a nitrogen protecting group. In certainembodiments, two R^(N1) are taken with the intervening atoms to form aheterocyclic ring.

As generally defined herein, each instance of R^(N2) is independentlyhydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogen protectinggroup, or two R^(N2) are taken with the intervening atoms to form aheterocyclic ring, or R^(N1) and R^(N2) are taken with the interveningatoms to form a heterocyclic ring. In certain embodiments, R^(N2) isnitrogen. In certain embodiments, R^(N2) is optionally substituted C₁₋₆alkyl. In certain embodiments, R^(N2) is substituted C₁₋₆ alkyl. Incertain embodiments, R^(N2) is unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(N2) is methyl. In certain embodiments, R^(N2) is ethyl.In certain embodiments, R^(N2) is a nitrogen protecting group. Incertain embodiments, two R^(N2) are taken with the intervening atoms toform a heterocyclic ring. In certain embodiments, R^(N1) and R^(N2) aretaken with the intervening atoms to form a heterocyclic ring.

In certain embodiments, R^(N1) and R^(N2) are the same. In certainembodiments, R^(N1) and R^(N2) are different. In certain embodiments,both R^(N1) and R^(N2) are hydrogen. In certain embodiments, R^(N1) ishydrogen and R^(N2) is not hydrogen. In certain embodiments, R^(N1) ishydrogen and R^(N2) is optionally substituted C₁₋₆ alkyl. In certainembodiments, R^(N1) is hydrogen and R^(N2) is substituted C₁₋₆ alkyl. Incertain embodiments, R^(N1) is hydrogen and R^(N2) is unsubstituted C₁₋₆alkyl. In certain embodiments, R^(N1) is hydrogen and R^(N2) is methyl,ethyl, or propyl. In certain embodiments, R^(N1) and R^(N2) are eachindependently optionally substituted C₁₋₆ alkyl. In certain embodiments,R^(N1) and R^(N2) are each independently substituted C₁₋₆ alkyl. Incertain embodiments R^(N1) and R^(N2) are each independentlyunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(N1) and R^(N2) areeach independently is methyl, ethyl, or propyl. In certain embodiments,R^(N1) and R^(N2) are taken with the intervening atoms to form aheterocyclic ring. In certain embodiments, R^(N1) and R^(N2) are takenwith the intervening atoms to form a six-membered heterocyclic ring. Incertain embodiments, R^(N1) and R^(N2) are taken with the interveningatoms to form a five-membered heterocyclic ring. In certain embodiments,R^(N1) and R^(N2) are taken with the intervening atoms to form abicyclic ring. In certain embodiments, R^(N1) and R^(N2) are eachindependently a nitrogen protecting group.

In certain embodiments, X₁ and X₂ are the same and R^(N1) and R^(N2) arethe same. In certain embodiments, X₁ and X₂ are Cl and R^(N1) and R^(N2)are hydrogen. In certain embodiments, X₁ and X₂ are Cl and R^(N1) andR^(N2) are optionally substituted alkyl. In certain embodiments, X₁ andX₂ are Cl and R^(N1) and R^(N2) are substituted alkyl. In certainembodiments, X₁ and X₂ are Cl and R^(N1) and R^(N2) are unsubstitutedalkyl. In certain embodiments, X₁ and X₂ are Cl and R^(N1) and R^(N2)are methyl, ethyl or propyl. In certain embodiments, X₁ and X₂ are Cland R^(N1) and R^(N2) are taken with the intervening atoms to form aheterocyclic ring. In certain embodiments, X₁ and X₂ are Cl and R^(N1)and R^(N2) are taken with the intervening atoms to form a five-memberedheterocyclic ring. In certain embodiments, X₁ and X₂ are Cl and R^(N1)and R^(N2) are taken with the intervening atoms to form a six-memberedheterocyclic ring. In certain embodiments, X₁ and X₂ are Cl and R^(N1)and R^(N2) are taken with the intervening atoms to form a bicyclic ring.

As generally defined herein, n is 1, 2, 3, 4, 5, or 6. In certainembodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5. In certain embodiments, n is 6.

In certain embodiments, the platinum complexes of Formula (I) areprodrugs of the platinum-based therapeutic agents. The Pt—O bond can becleaved by a reducing agent in vivo to release the active platinum-basedtherapeutic agent. In certain embodiments, the platinum complex ofFormula (I) is used as a crosslinker to prepare polymers for thecontrolled release of platinum-based agents. In certain embodiments, theplatinum complex of Formula (I) is used as a crosslinker to preparePt-BASP.

In certain embodiments, the platinum complex of Formula (I) is ofFormula (II):

or a salt thereof.

In certain embodiments, the platinum complex of Formula (I) is ofFormula (II-a):

or a salt thereof.

In certain embodiments, the platinum complex of Formula (I) is of theformula:

or a salt thereof.

The platinum complex of Formula (I) can be prepared using the generalmethodology shown in Scheme 1. Details of the synthetic procedures aredescribed in the Examples below.

In one embodiments, the invention provides methods of preparing aplatinum complex of Formula (I), the method comprising steps of:

(a) oxidizing a compound of Formula (s-1) with an oxidant

to yield a compound of Formula (s-2):

wherein:

X₁ is F, Cl, Br, or I;

X₂ is F, Cl, Br, or I;

each instance of R^(N1) and R^(N2) is independently hydrogen, optionallysubstituted C₁₋₆ alkyl, or a nitrogen protecting group; or two R^(N1)are taken with the intervening atoms to form a heterocyclic ring; or twoR^(N2) are taken with the intervening atoms to form a heterocyclic ring;or R^(N1) and R^(N2) are taken with the intervening atoms to form aheterocyclic ring; and n is 1, 2, 3, 4, 5, or 6; and

(b) coupling the compound of Formula (s-2) with a compound of Formula(s-3):

to yield a platinum complex of Formula (I).

In certain embodiments, the oxidant used in step (a) can oxidize Pt (II)to Pt (IV) with two hydroxyl groups under suitable oxidization condition(Hall et al., J. Biol. Inorg. Chem. 2003, 8, 726). In certainembodiments, the oxidant is H₂O₂.

In certain embodiments, an activator is present in the coupling reactionin step (b). The activator converts the compound of Formula (s-3) to anactivated ester for the coupling reaction. Examples of useful activatorsare dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC/HCl),diphenylphosphorylazide (DPPA), carbonyldiimidazole (CDI),diethylcyanophosphonate (DEPC),benzotriazole-1-yloxy-trispyrrolidinophosphonium (DIPCI),benzotriazole-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate(PyBOP), 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt),hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphonate (HATU),O-benzotriazole-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), 3,4-dihydro-3-hydrodi-4-oxa-1,2,3-benzotriazine (Dhbt). Incertain embodiments, the activator is DCC.

The activator is used in an amount of about 1 to 20 equivalents of thecompound of Formula (s-2). In certain embodiments, the activator is usedin an amount of about 1 to 10 equivalents. In certain embodiments, theactivator is used in an amount of about 1 to 5 equivalents.

Examples of useful solvents in the coupling reaction are DMSO, DMF,methylene chloride. The coupling reaction can be conducted at 0 to 50°C. In certain embodiments, the coupling reaction is conducted at roomtemperature for about 10 min to about 30 hours. In certain embodiments,the coupling reaction is conducted for about 15 minutes to about 24hours.

Macromonomers

In one aspect, the present invention provides a macromonomer of Formula(III),

or a salt thereof,wherein:

a is an integer from 1 to 10, inclusive;

b is an integer from 1 to 5 inclusive;

c is an integer from 30 to 100 inclusive;

e is 0, 1, 2, 3, or 4;

L is —O—, —S—, —NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—,—C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—,—NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C≡C—,—OC(R^(Lb))₂—, —C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—,—S(═)₂O—, —OS(═O)₂—, —S(═O)₂NR^(La)—, —NR^(La)S(═O)₂—, or an optionallysubstituted C₁₋₁₀ hydrocarbon chain, optionally wherein one or morecarbon units of the hydrocarbon chain is replaced with —O—, —S—,—NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C═C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—, wherein each instance of R^(La) isindependently hydrogen, optionally substituted C₁₋₁₀ alkyl, or anitrogen protecting group, and wherein each occurrence of R^(Lb) isindependently selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(Lb) groups are joined to form anoptionally substituted carbocyclic or optionally substitutedheterocyclic ring, or R^(La) and R^(Lb) are joined to form an optionallysubstituted heterocyclic ring; and

M is hydrogen or a therapeutic, diagnostic, or prophylactic agent.

As generally defined herein, a is an integer from 1 to 10, inclusive. Incertain embodiments, a is 1. In certain embodiments, a is 2. In certainembodiments, a is 3. In certain embodiments, a is 4. In certainembodiments, a is 5. In certain embodiments, a is 6. In certainembodiments, a is 7. In certain embodiments, a is 8. In certainembodiments, a is 9. In certain embodiments, a is 10.

As generally defined herein, b is an integer from 1 to 5, inclusive. Incertain embodiments, b is 1. In certain embodiments, b is 2. In certainembodiments, b is 3. In certain embodiments, b is 4. In certainembodiments, b is 5.

As generally defined herein, c is an integer from 30 to 100, inclusive.In certain embodiments, c is an integer from 40 to 90, inclusive. Incertain embodiments, c is an integer from 50 to 80, inclusive. Incertain embodiments, c is an integer from 60 to 70, inclusive. Incertain embodiments, c is from 65. In certain embodiments, c is from 66.In certain embodiments, c is from 67. In certain embodiments, c is from68. In certain embodiments, c is from 69. In certain embodiments, c isfrom 70.

As generally defined herein, e is 0, 1, 2, 3, or 4. In certainembodiments, e is 0. In certain embodiments, e is 1. In certainembodiments, e is 2. In certain embodiments, e is 3. In certainembodiments, e is 4.

As generally defined herein, linker L is —O—, —S—, —NR^(La)—,—NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R Lb)₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, —NR^(La)S(═O)₂—, or an optionally substituted C₁₋₁₀hydrocarbon chain, optionally wherein one or more carbon units of thehydrocarbon chain is replaced with —O—, —S—, —NR^(La)—, —NR^(La)C(═O)—,—C(═O)NR^(La)—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—,—NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C≡C—,—OC(R^(Lb))₂—, —C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—, wherein eachinstance of R^(La) is independently hydrogen, optionally substitutedC₁₋₁₀ alkyl, or a nitrogen protecting group, and wherein each occurrenceof R^(Lb) is independently selected from the group consisting ofhydrogen, halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl, or two R^(Lb) groups arejoined to form an optionally substituted carbocyclic or optionallysubstituted heterocyclic ring, or R^(La) and R^(Lb) are joined to forman optionally substituted heterocyclic ring. In certain embodiments, Lis an optionally substituted C₁₋₁₀ hydrocarbon chain, optionally whereinone or more carbon units of the hydrocarbon chain is replaced with —O—,—S—, —NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—,—OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—,trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—,—C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—,—OS(═O)₂—, —S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—. In certain embodiments,L is of the Formula (L-1):

wherein p is an integer from 1 to 10 inclusive. In certain embodiments,L is of the Formula (L-2):

wherein q is an integer of 1 to 10, inclusive; each instance of R^(E) ishalogen, —CN, —NO₂, —N₃, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted phenyl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, —OR^(A),—N(R^(B))₂, —SR^(A), —C(═O)R^(A), —C(═O)OR^(A), —C(═O)SR^(A),—C(═O)N(R^(B))₂, —C(═O)N(R^(B))N(R^(B))₂, —OC(═O)R^(A),—OC(═O)N(R^(B))₂, —NR^(B)C(═O)R^(A), NR^(B)C(═O)N(R^(B))₂,—NR^(B)C(═O)N(R^(B))N(R^(B))₂, —NR^(B)C(═O)OR^(A), —SC(═O)R^(A),—C(═NR^(B))R^(A), —C(═NNR^(B))R^(A), —C(═NORA)R^(A),—C(═NR^(B))N(R^(B))₂, —NR^(B)C(═NR^(B))R^(B), —C(═S)R^(A),—C(═S)N(R^(B))₂, —NR^(B)C(═S)R^(A), —S(═O)R^(A), —OS(═O)₂R^(A),—SO₂R^(A), —NR^(B)SO₂R^(A), and —SO₂N(R^(B))₂; wherein each R^(A) isindependently selected from the group consisting of hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl; and each R^(B) is independently selected fromthe group consisting of hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(B) groups are taken together with their intervening atoms to forman optionally substituted heterocyclic ring; and k is 0, 1, 2, 3, 4, or5. In certain embodiments, L is of the formula:

wherein q is an integer of 1 to 10, inclusive. In certain embodiments, Lis of the formula:

wherein q is an integer of 1 to 10, inclusive. In certain embodiments, Lis of the formula:

wherein q is 3. In certain embodiments, L is of the Formula (L-3):

wherein g is an integer from 1 to 10, inclusive. In certain embodiments,L is of the Formula (L-3):

wherein g is an integer from 1 to 5, inclusive. In certain embodiments,L is of the Formula (L-3):

wherein g is 3. In certain embodiments, L is of the Formula (L-4):

wherein h is an integer of 1 to 10, inclusive; each instance of R^(E) ishalogen, —CN, —NO₂, —N₃, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted phenyl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, —OR^(A),—N(R^(B))₂, —SR^(A), —C(═O)R^(A), —C(═O)OR^(A), —C(═O)SR^(A),—C(═O)N(R^(B))₂, —C(═O)N(R^(B))N(R^(B))₂, —OC(═O)R^(A),—OC(═O)N(R^(B))₂, —NR^(B)C(═O)R^(A), —NR^(B)C(═O)N(R^(B))₂,—NR^(B)C(═O)N(R^(B))N(R^(B))₂, —NR^(B)C(═O)OR^(A), —SC(═O)R^(A),—C(═NR^(B))R^(A), —C(═NNR^(B))R^(A), —C(═NORA)R^(A),—C(═NR^(B))N(R^(B))₂, —NR^(B)C(═NR^(B))R^(B), —C(═S)R^(A),—C(═S)N(R^(B))₂, —NR^(B)C(═S)R^(A), —S(═O)R^(A), —OS(═O)₂R^(A),—SO₂R^(A), —NR^(B)SO₂R^(A), and —SO₂N(R^(B))₂; wherein each R^(A) isindependently selected from the group consisting of hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl; and each R^(B) is independently selected fromthe group consisting of hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(B) groups are taken together with their intervening atoms to forman optionally substituted heterocyclic ring; and k is 0, 1, 2, 3, 4, or5. In certain embodiments, L is of the formula:

wherein h is an integer of 1 to 10, inclusive. In certain embodiments, Lis of the formula:

wherein h is an integer of 1 to 10, inclusive. In certain embodiments, Lis of the formula:

wherein h is 3. In certain embodiments, L is of the Formula:

wherein p is an integer from 1 to 10 inclusive. In certain embodiments,L is of the Formula (L-5):

wherein p is an integer from 1 to 5 inclusive. In certain embodiments, Lis of the Formula (L-5):

wherein p is 5.

In certain embodiments, the macromonomer of Formula (III) is of theFormula (III-a):

In certain embodiments, the macromonomer of Formula (III) is of theFormula (III-b):

In certain embodiments, the macromonomer of Formula (III) is of theFormula (III-c):

In certain embodiments, the macromonomer of Formula (III) is of theFormula (III-d):

As generally defined herein, M is hydrogen or a therapeutic, diagnostic,or prophylactic agent. In certain embodiments, M is hydrogen. In certainembodiments, M is a therapeutic, diagnostic, or prophylactic agent. Incertain embodiments, M is a therapeutic agent. Examples of therapeuticmoieties include, but are not limited to, antimicrobial agents,analgesics, antinflammatory agents, counterirritants, coagulationmodifying agents, diuretics, sympathomimetics, anorexics, antacids andother gastrointestinal agents; antiparasitics, antidepressants,antihypertensives, anticholinergics, stimulants, antihormones, centraland respiratory stimulants, drug antagonists, lipid-regulating agents,uricosurics, cardiac glycosides, electrolytes, ergot and derivativesthereof, expectorants, hypnotics and sedatives, antidiabetic agents,dopaminergic agents, antiemetics, muscle relaxants,para-sympathomimetics, anticonvulsants, antihistamines, beta-blockers,purgatives, antiarrhythmics, contrast materials, radiopharmaceuticals,antiallergic agents, tranquilizers, vasodilators, antiviral agents, andantineoplastic or cytostatic agents or other agents with anticancerproperties, or a combination thereof. Other suitable therapeuticmoieties include contraceptives and vitamins as well as micro- andmacronutrients. Still other examples include antiinfectives such asantibiotics and antiviral agents; analgesics and analgesic combinations;anorexics; antiheimintics; antiarthritics; antiasthmatic agents;anticonvulsants; antidepressants; antidiuretic agents; antidiarrleals;antihistamines; antiinflammatory agents; antimigraine preparations;antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics, antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhythmics; antihypertensives; diuretics; vasodilatorsincluding general coronary, peripheral and cerebral; central nervoussystem stimulants; cough and cold preparations, including decongestants;hormones such as estradiol and other steroids, includingcorticosteroids; hypnotics; immunosuppressives; muscle relaxants;parasympatholytics; psychostimulants; sedatives; and tranquilizers; andnaturally derived or genetically engineered proteins, polysaccharides,glycoproteins, or lipoproteins. In certain embodiments, M is ananti-cancer agent. Anti-cancer agents encompass biotherapeuticanti-cancer agents as well as chemotherapeutic agents. Exemplarybiotherapeutic anti-cancer agents include, but are not limited to,interferons, cytokines (e.g., tumor necrosis factor, interferon α,interferon γ), vaccines, hematopoietic growth factors, monoclonalserotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1,2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) andantibodies (e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab),ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR(tositumomab)). Exemplary chemotherapeutic agents include, but are notlimited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol),LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g.flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin(BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellinA (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide),platinum containing compounds (e.g. cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine,and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent)docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin),polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex,CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxelbound to the erbB2-recognizing peptide EC-1), and glucose-conjugatedpaclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposidephosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate),IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin,ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g.hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil(5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil,capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosinearabinoside, and fludarabine), purine analogs (e.g., mercaptopurine andThioguanine), Vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060),isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins(e.g. 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.,staurosporine), actinomycin (e.g. actinomycin D, dactinomycin),bleomycin (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracycline(e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g., verapamil), Ca²⁺ ATPase inhibitors (e.g.,thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinaseinhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib(RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib(TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B,STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701),neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib,SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib(ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab(HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab(ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib(TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab(CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®),ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607,ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265,DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121,XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib(VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779),everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055(AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (SanofiAventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), andOSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin,pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,aminopterin, and hexamethyl melamine. In certain embodiments, M iscamptothecin or doxorubicin.

In certain embodiments, M is a diagnostic agent. Exemplary diagnosticagents include, but are not limited to, fluorescent molecules; gases;metals; commercially available imaging agents used in positron emissionstomography (PET), computer assisted tomography (CAT), single photonemission computerized tomography, x-ray, fluoroscopy, and magneticresonance imaging (MRI); and contrast agents. Examples of suitablematerials for use as contrast agents in MRI include gadolinium chelates,as well as iron, magnesium, manganese, copper, and chromium. Examples ofmaterials useful for CAT and x-ray imaging include iodine-basedmaterials. In certain embodiments, the diagnostic agent is used inmagnetic resonance imaging (MRI), such as iron oxide particles orgadolinium complexes. Gadolinium complexes that have been approved forclinical use include gadolinium chelates with DTPA, DTPA-BMA, DOTA andHP-DO3A which are reviewed in Aime, et al. (Chemical Society Reviews(1998), 27:19-29), the entire teachings of which are incorporated hereinby reference.

In certain embodiments, M is a prophylactic agent. Prophylactic agentsthat can be included in the conjugates of the invention include, but arenot limited to, antibiotics, nutritional supplements, and vaccines.Vaccines may comprise isolated proteins or peptides, inactivatedorganisms and viruses, dead organisms and viruses, genetically alteredorganisms or viruses, and cell extracts. Prophylactic agents may becombined with interleukins, interferon, cytokines, and adjuvants such ascholera toxin, alum, Freund's adjuvant.

M can be conjugated to the macromonomer using any suitable conjugationtechnique. For instance, EDC-NHS chemistry(1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride andN-hydroxysuccinimide), or a reaction involving a maleimide or acarboxylic acid, which can be conjugated to one end of a thiol, anamine, or a similarly functionalized polyether. The conjugation can beperformed in an organic solvent, such as, but not limited to, methylenechloride, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran,acetone, or the like. Specific reaction conditions can be determined bythose of ordinary skill in the art using no more than routineexperimentation.

In another set of embodiments, a conjugation reaction may be performedby reacting the agent that includes a hydroxyl, thiol, or amino groupwith a polymer comprising a carboxylic acid functional group. Such areaction may occur as a single-step reaction, i.e., the conjugation isperformed with or without using intermediates such asN-hydroxysuccinimide or a maleimide. The conjugation reaction betweenthe amine-containing, thiol-containing, or hydroxyl-containing moietyand the carboxylic acid-terminated polymer may be achieved in oneembodiment, by adding the amine-containing, thoil-containing, orhydroxyl-containing moiety, solubilized in an organic solvent such as,but not limited to, dichloromethane, acetonitrile, chloroform,tetrahydrofuran, acetone, formamide, dimethylformamide, pyridines,dioxane, or dimethysulfoxide, to a solution containing the carboxylicacid-terminated polymer. The carboxylic acid-terminated polymer may becontained within an organic solvent such as, but not limited to,dichloromethane, acetonitrile, chloroform, dimethylformamide,tetrahydrofuran, or acetone. Reaction between the amine-containingmoiety and the carboxylic acid-terminated polymer may occurspontaneously in some cases. Unconjugated macromonomers may be washedaway after such reactions, and the polymer may be precipitated insolvents such as, for instance, ethyl ether, hexane, methanol, orethanol.

In some cases, the Pt-BASPs are of the form of nanoparticles, i.e., theparticle have a characteristic dimension of less than about 1micrometer, where the characteristic dimension of a particle is thediameter of a perfect sphere having the same volume as the particle. Incertain embodiments, the Pt-BASP particle has a characteristic dimensionof less than about 300 nm. In certain embodiments, the Pt-BASP particlehas a characteristic dimension of less than about 200 nm. In certainembodiments, the Pt-BASP particle has a characteristic dimension of lessthan about 150 nm. In certain embodiments, the Pt-BASP particle has acharacteristic dimension of less than about 100 nm. In certainembodiments, the Pt-BASP particle has a characteristic dimension of lessthan about 50 nm. In certain embodiments, the Pt-BASP particle has acharacteristic dimension of less than about 30 nm. In certainembodiments, the Pt-BASP particle has a characteristic dimension of lessthan about 20 nm. In certain embodiments, the Pt-BASP particle has acharacteristic dimension of less than about 10 nm. In certainembodiments, the Pt-BASP particle has a characteristic dimension between6 and 250 nm, inclusive. In certain embodiments, the Pt-BASP particlehas a characteristic dimension between 8 and 200 nm, inclusive. Incertain embodiments, the Pt-BASP particle has a characteristic dimensionbetween 12 and 200 nm, inclusive. In certain embodiments, the Pt-BASPparticle has a characteristic dimension between 50 and 200 nm,inclusive.

In certain embodiments, the macromonomer of Formula (III) is of theformula:

In certain embodiments, the macromonomer of Formula (III) is of theformula:

In certain embodiments, the macromonomer of Formula (III) is acamptothecin macromonomer of the formula:

In certain embodiments, the macromonomer of Formula (III) is acamptothecin macromonomer of the formula:

In certain embodiments, the macromonomer of Formula (III) is doxorubicinmacromonomer of the formula:

In certain embodiments, the macromonomer of Formula (III) is doxorubicinmacromonomer of the formula:

The macromonomers of Formula (III) can be prepared using the generalmethods shown in J. Johnson et al., Macromolecules, 2010, 43 (24),10326-10335.

Platinum-Based Brush-Arm Star Polymers (Pt-BASPs)

The present invention provides platinum-based brush-arm star polymers(Pt-BASP) using the “brush-first” ring-opening metathesis polymerization(ROMP). The brush-first method involves sequential copolymerization oftwo functional monomers, a polymeric macromonomer (MM) followed by amultifunctional crosslinker, to generate a unimolecular micelle-likenanostructure with a core comprised of the crosslinker and a coronacomprised of the MM. For example, FIG. 2 shows the exemplary synthesisof Pt-BASPs via a route that combines the “graft-through” and“arm-first” methodologies. Homopolymerization of macromonomer 4catalyzed by third-generation Grubb's catalyst C1 generated livingpolymerization chains, which then served as “brush initiators” toinitiate reaction with the cross-linker XL3, forming stars Pt-BASP withcovalently bound Pt(IV) complex cores. Under the reducing environment incells, the cores constructed by Pt(IV) complexes will be reduced, whichleads to the release of Pt complexes and degradation of the starpolymers.

A Pt-BASP described herein includes a cisplatin moiety attached to therest of the Pt-BASP through ester bonds. Cisplatin is a clinicallyapproved chemotherapeutic agent that includes a platinum(IV) (Pt(IV))core. Pt(IV) diester derivatives have been widely applied as prodrugsfor cisplatin (Hall, M. D.; Hambley, T. W. Coord. Chem. Rev. 2002, 232,49; Nishiyama et al. Cancer Res. 2003, 63, 8977; Dhar, S.; Gu, F. X.;Langer, R.; Farokhzad, O. C.; Lippard, S. J. Proc. Natl. Acad. Sci.U.S.A. 2008, 105, 17356; Dhar, S.; Daniel, W. L.; Giljohann, D. A.;Mirkin, C. A.; Lippard, S. J. J. Am. Chem. Soc. 2009, 131, 14652;Plummer et al. Br. J. Cancer 2011, 104, 593). Pt(IV) diesters releasecytotoxic platinum(II) (Pt(II)) species upon glutathione-inducedintracellular reduction.

In addition to cisplatin, a Pt-BASP described herein may include one ormore additional agents that are not cisplatin to form multi-agent-loaded(e.g., multi-drug-loaded) Pt-BASPs. The described Pt-BASPs areadvantageous over known nanoparticle (NP)-based delivery systems.NP-based combination cancer therapy has the potential to overcome thetoxicity and poorly controlled dosing of traditional systemiccombination therapies (Hu, C. M. J.; Zhang, L. F. Biochem. Pharmacol.2012, 83, 1104; Yan, Y.; Bjornmalm, M.; Caruso, F. ACS Nano 2013, 7,9512; Ma, L.; Kohli, M.; Smith, A. ACS Nano 2013, 7, 9518). ThoughNP-based therapeutics for cancer therapy have been the subject ofnumerous investigations over the past several decades (Duncan, R. Nat.Rev. Drug Discovery 2003, 2, 347; Peer et al. Nat. Nanotechnol. 2007, 2,751; Wolinsky, J. B.; Grinstaff, M. W. Adv. Drug Delivery Rev. 2008, 60,1037; Davis, M. E.; Chen, Z.; Shin, D. M. Nat. Rev. Drug Discovery 2008,7, 771; Kwon, G. S.; Kataoka, K. Adv. Drug Delivery Rev. 2012, 64, 237),ratiometric, synchronized release of multiple drugs from single NPscaffolds remains a challenge (Sengupta et al. Nature 2005, 436, 568;Lammers et al. Biomaterials 2009, 30, 3466; Kolishetti, N.; Dhar, S.;Valencia, P. M.; Lin, L. Q.; Karnik, R.; Lippard, S. J.; Langer, R.;Farokhzad, O. C. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 17939; Aryal,S.; Hu, C. M. J.; Zhang, L. F. Mol. Pharm. 2011, 8, 1401). Many reportednanoparticle architectures for delivery, e.g., liposomes, micelles, anddendrimers, are not readily amenable to controlled incorporation andrelease of multiple drugs.

In contrast, the Pt-BASPs described herein are able to deliver multipleagents (e.g., cisplatin and one or more other agents) ratiometrically.The agents included in a Pt-BASP may show different therapeutic,diagnostic, and/or prophylactic effects on a subject, tissue, or cell.For example, a Pt-BASP may include two or more therapeutic agents(including cisplatin), and the therapeutic agents may show differentanti-proliferative activities (e.g., anti-cancer activities) at eachtherapeutic agent's maximum tolerated dose (MTD). A key benefit ofsingle nanoparticle combination therapy is the ability to delivermultiple drugs at a precise ratio to a subject, tissue, or cell, whileminimizing undesired effects (e.g., toxicity) associated with multipledrug combinations. To achieve the maximum therapeutic index in amulti-drug combination therapy, simultaneous dosing of each drug at ornear each drug's MTD would be ideal. A Pt-BASP described herein mayinclude multiple drugs at or near each drug's MTD before the Pt-BASP isdelivered to a subject, tissue, or cell, release the multiple drugs ator near each drug's MTD into the subject, tissue, or cell afterdelivery, and therefore achieve the maximum therapeutic index. Incertain embodiments, a Pt-BASP described herein includes camptothecin(CPT) and cisplatin. In certain embodiments, a Pt-BASP described hereinincludes doxorubicin (DOX) and cisplatin. In certain embodiments, aPt-BASP described herein includes CPT, DOX, and cisplatin. CPT, DOX, andcisplatin have shown non-overlapping toxicity profiles (Devita et al.Ann. Intern. Med. 1970, 73, 881; Al-Lazikani, B.; Banerji, U.; Workman,P. Nat. Biotechnol. 2012, 30, 679). A serious dose-limiting side effectfrom doxorubicin may arise due to cardiotoxicity (Singal, P. K.;Iliskovic, N. N. Engl. J. Med. 1998, 339, 900), while those fromcisplatin and camptothecin may result from neurotoxicity (Mollman, N.Engl. J. Med. 1990, 322, 126) and myelosuppression or hemorrhagiccystitis (Pizzolato, J. F.; Saltz, L. B. Lancet 2003, 361, 2235),respectively. In certain embodiments, a Pt-BASP described hereinincludes CPT, DOX, and cisplatin, wherein the molar ratio ofCPT:DOX:cisplatin in the Pt-BASP is substantially equal to the ratio ofthe MTD of CPT:the MTD of DOX:the MTD of cisplatin against a cell (e.g.,a cancer cell). In certain embodiments, the molar ratio ofCPT:DOX:cisplatin in a Pt-BASP that includes CPT, DOX, and cisplatin issubstantially equal to the ratio of (the MTD of CPT)×2:(the MTD ofDOX)×2:the MTD of cisplatin against a cell (e.g., a cancer cell)(Caiolfa et al. J. Controlled Release 2000, 65, 105; MacKay, J. A.;Chen, M. N.; McDaniel, J. R.; Liu, W. G.; Simnick, A. J.; Chilkoti, A.Nat. Mater 2009, 8, 993; Chang, C. L.; Hsu, Y. T.; Wu, C. C.; Lai, Y.Z.; Wang, C. N.; Yang, Y. C.; Wu, T. C.; Hung, C. F. Cancer Res. 2013,73, 119). In certain embodiments, the molar ratio of CPT:DOX:cisplatinin a Pt-BASP that includes CPT, DOX, and cisplatin is about2.07:0.83:3.00. It has been shown that Pt-BASPs (e.g., polymer P3) thatinclude CPT, DOX, and cisplatin at a molar ratio of about 2.07:0.83:3.00outperformed Pt-BASPs that include only one or two of CPT, DOX, andcisplatin, in in vitro cell viability studies using ovarian cancer(OVCAR3) cells.

The Pt-BASPs described herein are also able to deliver multiple agentsorthogonally. Different chemical and/or physical conditions may beemployed to individually release the multiple agents upon delivery. Theconvergent synthesis of Pt-BASPs allow the attachment of differentagents to the Pt-BASPs through different linkers (e.g., linkerscleavable by reduction, such as Pt—O bonds; hydrolysable linkers, suchas ester bonds; and photo-cleavable linkers, such as the moiety

wherein the moiety may be further substituted). For example, cisplatinmay be released from a Pt-BASP by a reduction reaction of the Pt—O bondsof cisplatin; and other agents included in the Pt-BASP may be releasedfrom the Pt-BASP under chemical and/or physical conditions that aredifferent from the reduction reaction. In certain embodiments, an agent,other than cisplatin, included in a Pt-BASP is released from the Pt-BASPby hydrolysis (e.g., hydrolysis under acidic conditions). In certainembodiments, an agent, other than cisplatin, included in a Pt-BASP isreleased from the Pt-BASP by irradiation with ultraviolet light (UV).For example, orthogonal release of of CPT, DOX, and cisplatin frompolymer P3 may be achieved by hydrolyzation (which releases CPT),irradiation with UV (which releases DOX), and reduction (which releasescisplatin), wherein the hydrolyzation, irradiation, and reduction may beperformed in any order and at the same time or different times.

The Pt-BASPs described herein can be directly constructed usingcarefully designed drug-conjugates as building blocks, and noself-assembly is required for preparing the Pt-BASPs. The methods forpreparing the Pt-BASPs described herein involves ring-opening metathesispolymerization (ROMP) (Liu et al. J. Am. Chem. Soc. 2012, 134, 16337;Liu, J.; Gao, A. X.; Johnson, J. A. J Vis Exp 2013, e50874). In certainembodiments, the Pt-BASPs described herein are prepared bypolymerization of norbornene-terminated macromonomers (MMs) followed byin situ crosslinking with bis-norbomene crosslinkers. The preparationmethods described herein are versatile and have little limitations,e.g., in terms of the different agents that can be built into thePt-BASPs. In certain embodiments, an agent that can be built into thePt-BASPs includes addressable functional groups that are compatible withROMP. In certain embodiments, the invention provides Pt-BASPs preparedby Method A including the steps of:

(a) reacting a macromonomer of Formula (III) (e.g., a macromonomer ofFormula (III))

with a metathesis catalyst to form a polymerization mixture; and

(b) mixing the polymerization mixture from step (a) with a solution of aplatinum complex of Formula (I):

In certain embodiments, M in the macromonomer is not cisplatin. InMethod A, step (a) may be performed in the presence of anon-agent-loaded MM, such as a macromonomer of Formula (IV):

In certain embodiments, the molar ratio of a non-agent-loaded MM to thecombined agents (including cisplatin) is about 0.01:1, about 0.3:1,about 0.67:1, about 1:1, about 1.5:1, about 3:1, about 10:1, about 30:1,or about 100:1. In certain embodiments, the molar ratio of anon-agent-loaded macromonomer to the combined agents (includingcisplatin) is about 0.67:1.

In certain embodiments, the provided Pt-BASPs are loaded with more thanone therapeutic, diagnostic, or prophylactic agents other than cisplatinand can be prepared by Method B including the steps of:

(a) reacting a first macromonomer of Formula (III) with a secondmacromonomer of Formula (III)

in the presence of a metathesis catalyst to form a polymerizationmixture, wherein M in the first macromonomer is different from M in thesecond macromonomer; and

(b) mixing the polymerization mixture from step (a) with a solution of aplatinum complex of Formula (I):

wherein a, b, c, e, M, L, X₁, X₂, R^(N1), R^(N2), and n are as definedherein.

In Method B, step (a) may be performed in the presence of anon-agent-loaded MM, such as a macromonomer of Formula (IV):

In certain embodiments, the non-agent-loaded MM is macromonomer PEG-MM.In certain embodiments of the Pt-BASPs loaded with more than onetherapeutic, diagnostic, or prophylactic agents, Ms in the first andsecond macromonomers are different. In certain embodiments, Ms in thefirst and second macromonomers are not cisplatin. In certain embodimentsof the Pt-BASPs loaded with more than one therapeutic, diagnostic, orprophylactic agents, Ms in the first and second macromonomers aredifferent therapeutic agents. In certain embodiments of the Pt-BASPsloaded with more than one therapeutic, diagnostic, or prophylacticagents, M in the first macromonomer is camptothecin, and M in the secondmacromonomer is doxorubicin. In certain embodiments of the Pt-BASPsloaded with more than one therapeutic, diagnostic, or prophylacticagents, M in the first macromonomer is doxorubicin, and M in the secondmacromonomer is camptothecin.

The synthesis of Pt-BASPs involves ROMP of MM in step (a) and ROMP ofthe platinum complex in step (b). In certain embodiments, the ROMPcatalyst is a tungsten (W), molybdenum (Mo), or ruthenium (Ru) catalyst.In certain embodiments, the ROMP catalyst is a ruthenuim catalyst. ROMPcatalysts useful in the synthetic methods described herein includecatalysts as depicted below, and as described in Grubbs et al., Acc.Chem. Res. 1995, 28, 446-452; U.S. Pat. No. 5,811,515; Schrock et al.,Organometallics (1982) 1 1645; Gallivan et al., Tetrahedron Letters(2005) 46:2577-2580; Furstner et al., J. Am. Chem. Soc. (1999) 121:9453;and Chem. Eur. J. (2001) 7:5299; the entire contents of each of whichare incorporated herein by reference.

In certain embodiments, the ROMP catalyst is a Grubbs catalyst. Incertain embodiments, the Grubbs catalyst is selected from the groupconsisting of:

-   Benzylidenebis-(tricyclohexylphosphine)-dichlororuthenium (X=Cl);-   Benzylidenebis-(tricyclohexylphosphine)-dibromoruthenium (X=Br);-   Benzylidenebis-(tricyclohexylphosphine)-diiodoruthenium (X=I);

-   1,3-(Bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)    (tricyclohexyl-phosphine)ruthenium (X=Cl; R=cyclohexyl);-   1,3-(Bis(mesityl)-2-imidazolidinylidene)dibromo-(phenylmethylene)    (tricyclohexyl-phosphine)ruthenium (X=Br; R=cyclohexyl);-   1,3-(Bis(mesityl)-2-imidazolidinylidene)diiodo-(phenylmethylene)    (tricyclohexyl-phosphine)ruthenium (X=I; R=cyclohexyl);-   1,3-(Bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)    (triphenylphosphine)ruthenium (X=Cl; R=phenyl);-   1,3-(Bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)    (tribenzylphosphine)ruthenium (X=Cl; R=benzyl);

In certain embodiments, the ROMP catalyst is a Grubbs-Hoveyda catalyst.In certain embodiments, the Grubbs-Hoveyda catalyst is selected from thegroup consisting of:

In certain embodiments, the ROMP catalyst is selected from the groupconsisting of:

In certain embodiments, the ROMP catalyst is of the formula:

The ROMP can be conducted in one or more aprotic solvents. The term“aprotic solvent” means a non-nucleophilic solvent having a boilingpoint range above ambient temperature, preferably from about 25° C. toabout 190° C. at atmospheric pressure. In certain embodiments, theaprotic solvent has a boiling point from about 80° C. to about 160° C.at atmospheric pressure. In certain embodiments, the aprotic solvent hasa boiling point from about 80° C. to about 150° C. at atmosphericpressure. Examples of such solvents are methylene chloride,

The ROMP can be quenched with a vinyl ether of the formula

Each of R^(V1), R^(V2), R^(V3), and R^(V4) is independently optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted phenyl, optionally substituted heterocyclyl, or optionallysubstituted heteroaryl. In certain embodiments, R^(V1) is optionallysubstituted alkyl, and R^(V2), R^(V3), and R^(V4) are hydrogen. Incertain embodiments, R^(V1) is unsubstituted alkyl, and R^(V2), R^(V3),and R^(V4) are hydrogen. In certain embodiments, R^(V1) is substitutedalkyl, and R^(V2), R^(V3), and R^(V4) are hydrogen. In certainembodiments, R^(V1) is methyl, and R^(V2), R^(V3), and R^(V4) arehydrogen. In certain embodiments, R^(V1) is ethyl, and R^(V2), R^(V3),and R^(V4) are hydrogen. In certain embodiments, R^(V1) is propyl, andR^(V2), R^(V3), and R^(V4) are hydrogen. In certain embodiments, R^(V1)is optionally substituted alkenyl, and R^(V2), R^(V3), and R^(V4) arehydrogen. In certain embodiments, R^(V1) is unsubstituted alkenyl, andR^(V2), R^(V3), and R^(V4) are hydrogen. In certain embodiments, R^(V1)is vinyl, and R^(V2), R^(V3), and R^(V4) are hydrogen. In certainembodiments, at least one of R^(V1), R^(V2), R^(V3), and R^(V4) isconjugated with a diagnostic agent as defined above. In certainembodiments, the ROMP is quenched by ethyl vinyl ether. Excess ethylvinyl ether can be removed from the Pt-BASPs by vacuum.

The Pt-BASPs can be multi-agent loaded star polymers. In certainembodiments, the inventive Pt-BASPs are capable of releasing multiplechemotherapeutic agents for combination therapy. In certain embodiments,the Pt-BASPs are capable of releasing two chemotherapeutic agents. Incertain embodiments, the Pt-BASPs are capable of releasing threechemotherapeutic agents. In certain embodiments, the Pt-BASPs arecapable of releasing four chemotherapeutic agents. In certainembodiments, the Pt-BASPs are capable of releasing five chemotherapeuticagents. In certain embodiments, the Pt-BASPs incorporate only aplatinum-based agent which is introduced from the platinum-based complexcrosslinkers. In certain embodiments, the inventive Pt-BASPs incorporateonly cisplatin. In certain embodiments, the Pt-BASPs incorporate one ormore therapeutic, diagnostic, or prophylactic agents. The one or moretherapeutic, diagnostic, or prophylactic agents are introduced frommacromonomers in the synthesis of Pt-BASPs. In certain embodiments, atherapeutic agent is incorporated in the macromonomer. In certainembodiments, an anti-cancer agent is incorporated in the macromonomer.In certain embodiments, the macromonomer is camptothecin (CPT)macromonomer. In certain embodiments, the macromonomer is doxorubicin(DOX) macromonomer. In certain embodiments, the inventive Pt-BASPsincorporate a platinum therapeutic agent and CPT. In certainembodiments, the inventive Pt-BASPs incorporate cisplatin and CPT. Incertain embodiments, the inventive Pt-BASPs incorporate a platinumtherapeutic agent, CPT, and DOX. In certain embodiments, the inventivePt-BASPs incorporate cisplatin, CPT, and DOX. In certain embodiments,the one or more therapeutic, diagnostic, or prophylactic agents areconnected to Pt-BASPs by a photocleavable linker. When the Pt-BASP isirradiated with light, DOX is released, and the IC50 of the Pt-BASPshave a lower value. In certain embodiments, the inventive Pt-BASPsincorporate a diagnostic agent and a platinum therapeutic agent. Incertain embodiments, the inventive Pt-BASPs incorporate a prophylacticagent and a platinum therapeutic agent.

In certain embodiments, the Pt-BASPs are biodegradable, i.e., thepolymer is able to degrade, chemically and/or biologically, within aphysiological environment, such as within the body. For instance, thepolymer may be one that hydrolyzes spontaneously upon exposure to water(e.g., within a subject), the polymer may degrade upon exposure to heat(e.g., at temperatures of about 37° C.). Degradation of a polymer mayoccur at varying rates, depending on the polymer or copolymer used. Forexample, the half-life of the polymer (the time at which 50% of thepolymer is degraded into monomers and/or other nonpolymeric moieties)may be on the order of days, weeks, months, or years, depending on thepolymer. The polymers may be biologically degraded, e.g., by enzymaticactivity or cellular machinery, in some cases, for example, throughexposure to a lysozyme (e.g., having relatively low pH). In some cases,the polymers may be broken down into monomers and/or other nonpolymericmoieties that cells can either reuse or dispose of without significanttoxic effect on the cells (for example, polylactide may be hydrolyzed toform lactic acid, polyglycolide may be hydrolyzed to form glycolic acid,etc.).

In certain embodiments, the solvents in step (a) is be same as thesolvent of the platinum complex solution in step (b). In certainembodiments, the solvents in step (a) is different from the solvent ofthe platinum complex solution in step (b). Exemplary solvents for step(a) and platinum complex solution include, but are not limited to,methylene chloride, acetonitrile, chloroform, dimethylformamide,tetrahydrofuran, and acetone. Specific reaction conditions can bedetermined by those of ordinary skill in the art using no more thanroutine experimentation.

In certain embodiments of one type of macromonomer in Pt-BASPs, theamount of all the macromonomers, the platinum complex crosslinker, andthe metathesis catalyst is of the molar ratio m:N:1, wherein m is aninteger from 1 to 20, inclusive; and N is an integer from 1 to 20,inclusive. In certain embodiments, m is an integer from 3 to 12inclusive. In certain embodiments, m is 1. In certain embodiments, m is2. In certain embodiments, m is 3. In certain embodiments, m is 4. Incertain embodiments, m is 5. In certain embodiments, m is 6. In certainembodiments, m is 7. In certain embodiments, m is 8. In certainembodiments, m is 9. In certain embodiments, m is 10. In certainembodiments, m is 11. In certain embodiments, m is 12. In certainembodiments, N is an integer from 1 to 10 inclusive. In certainembodiments, N is 1. In certain embodiments, N is 2. In certainembodiments, N is 3. In certain embodiments, N is 4. In certainembodiments, N is 5. In certain embodiments, N is 6. In certainembodiments, N is 7. In certain embodiments, N is 8. In certainembodiments, N is 9. In certain embodiments, N is 10. In certainembodiments, the amount of macromonomer, platinum complex crosslinker,and metathesis catalyst is of the ratio 5:3:1. In certain embodiments,the amount of macromonomer, platinum complex crosslinker, and metathesiscatalyst is of the molar ratio 5:5:1. In certain embodiments, the amountof macromonomer, platinum complex crosslinker, and metathesis catalystis of the molar ratio 5:7:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 7:3:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 7:5:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 7:7:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 11:1:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 11:3:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 11:5:1.

In certain embodiments of multi-agent loaded Pt-BASPs, the amount of thefirst macromonomer, second macromonomer, and platinum complexcrosslinker is of the molar ratio of m1:m2:N, wherein m1 and m2 are eachindependently an integer from 1 to 20, inclusive; and N is an integerfrom 1 to 20, inclusive. In certain embodiments, the amount of the firstmacromonomer, second macromonomer, and platinum complex crosslinker isof the molar ratio of 3:4:3. In certain embodiments, the amount of thefirst macromonomer, second macromonomer, and platinum complexcrosslinker is of the molar ratio of 4:3:3. In certain embodiments ofmore than one types of macromonomers in the multi-agent loaded Pt-BASPs,the amount of the first macromonomer, second macromonomer, and platinumcomplex crosslinker is of the molar ratio of m1:m2:N:1, wherein m1 andm2 are each independently an integer from 1 to 20, inclusive; and N isan integer from 1 to 20, inclusive. In certain embodiments, the amountof the first macromonomer, second macromonomer, and platinum complexcrosslinker is of the molar ratio of 3:4:3:1. In certain embodiments,the amount of the first macromonomer, second macromonomer, and platinumcomplex crosslinker is of the molar ratio of 4:3:3:1.

Exposure to physiologically relevant conditions can lead to the Pt-BASPsdegradation and controlled, extended release of platinum-based agents.In certain embodiments, the release rate can increased by addition ofGSH. In vitro cytotoxicity assays demonstrates that Pt-BASPs effectivelykill cancer cells (FIG. 5).

Pharmaceutical Compositions, Kits, and Administration

The present invention provides pharmaceutical compositions comprisingPt-BASPs, as described herein, and optionally a pharmaceuticallyacceptable excipient. In certain embodiments, the Pt-BASPs are providedin an effective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is a prophylacticallyeffective amount.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the Pt-BASPs into association witha carrier and/or one or more other accessory ingredients, and then, ifnecessary and/or desirable, shaping and/or packaging the product into adesired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage such as, for example, one-half or one-third ofsuch a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g. acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)),long chain amino acid derivatives, high molecular weight alcohols (e.g.stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate,ethylene glycol distearate, glyceryl monostearate, and propylene glycolmonostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium,powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acidesters (e.g. polyoxyethylene sorbitan monolaurate (Tween® 20),polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitanmonooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitanmonostearate (Span® 60), sorbitan tristearate (Span® 65), glycerylmonooleate, sorbitan monooleate (Span® 80)), polyoxyethylene esters(e.g. polyoxyethylene monostearate (MYRJ 45), polyoxyethylenehydrogenated castor oil, polyethoxylated castor oil, polyoxymethylenestearate, and Solutol), sucrose fatty acid esters, polyethylene glycolfatty acid esters (e.g. Cremophor™), polyoxyethylene ethers, (e.g.polyoxyethylene lauryl ether (BRIJ 30)), poly(vinyl-pyrrolidone),diethylene glycol monolaurate, triethanolamine oleate, sodium oleate,potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium laurylsulfate, PLURONIC F-68, Poloxamer-188, cetrimonium bromide,cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/ormixtures thereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives. In certainembodiments, the preservative is an antioxidant. In other embodiments,the preservative is a chelating agent.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT PLUS,PHENONIP, methylparaben, GERMALL 115, GERMABEN II, NEOLONE, KATHON, andEUXYL.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor™,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions which can be used include polymericsubstances and waxes. Solid compositions of a similar type can beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugar as well as high molecular weightpolethylene glycols and the like.

Dosage forms for topical and/or transdermal administration of a compoundof this invention may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, thePt-BASPs are admixed under sterile conditions with a pharmaceuticallyacceptable carrier and/or any needed preservatives and/or buffers as canbe required. Additionally, the present invention contemplates the use oftransdermal patches, which often have the added advantage of providingcontrolled delivery of an active ingredient to the body. Such dosageforms can be prepared, for example, by dissolving and/or dispensing theactive ingredient in the proper medium. Alternatively or additionally,the rate can be controlled by either providing a rate controllingmembrane and/or by dispersing the active ingredient in a polymer matrixand/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle which pierces the stratumcorneum and produces a jet which reaches the dermis are suitable. Jetinjection devices are described, for example, in U.S. Pat. Nos.5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratethe compound in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil-in-water and/or water-in-oil emulsions such as creams,ointments, and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations may, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. Formulations for topicaladministration may further comprise one or more of the additionalingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles ofPt-BASPs described herein. Such compositions are conveniently in theform of dry powders for administration using a device comprising a drypowder reservoir to which a stream of propellant can be directed todisperse the powder and/or using a self-propelling solvent/powderdispensing container.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may provide the Pt-BASPs in the form of droplets of a solutionand/or suspension. Such formulations can be prepared, packaged, and/orsold as aqueous and/or dilute alcoholic solutions and/or suspensions,optionally sterile, comprising the active ingredient, and mayconveniently be administered using any nebulization and/or atomizationdevice. Such formulations may further comprise one or more additionalingredients including, but not limited to, a flavoring agent such assaccharin sodium, a volatile oil, a buffering agent, a surface activeagent, and/or a preservative such as methylhydroxybenzoate. The dropletsprovided by this route of administration may have an average diameter inthe range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition of theinvention. Another formulation suitable for intranasal administration isa coarse powder comprising the Pt-BASPs and having an average particlefrom about 0.2 to 500 micrometers. Such a formulation is administered byrapid inhalation through the nasal passage from a container of thepowder held close to the nares.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Pt-BASPs provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular subject or organism will dependupon a variety of factors including the disease being treated and theseverity of the disorder; the activity of the specific active ingredientemployed; the specific composition employed; the age, body weight,general health, sex and diet of the subject; the time of administration,route of administration, and rate of excretion of the specific activeingredient employed; the duration of the treatment; drugs used incombination or coincidental with the specific active ingredientemployed; and like factors well known in the medical arts.

The Pt-BASPs and compositions provided herein can be administered by anyroute, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration).

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

In certain embodiments, an effective amount of the inventive polymer foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the inventive polymer may be at dosage levelssufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, fromabout 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg toabout 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, fromabout 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionalpharmaceutical agents. The compounds or compositions can be administeredin combination with additional pharmaceutical agents that improve theirbioavailability, reduce and/or modify their metabolism, inhibit theirexcretion, and/or modify their distribution within the body. It willalso be appreciated that the therapy employed may achieve a desiredeffect for the same disorder, and/or it may achieve different effects.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional pharmaceutical agents,which may be useful as, e.g., combination therapies. Pharmaceuticalagents include therapeutically active agents. Pharmaceutical agents alsoinclude prophylactically active agents. Each additional pharmaceuticalagent may be administered at a dose and/or on a time schedule determinedfor that pharmaceutical agent. The additional pharmaceutical agents mayalso be administered together with each other and/or with the compoundor composition described herein in a single dose or administeredseparately in different doses. The particular combination to employ in aregimen will take into account compatibility of the inventive compoundwith the additional pharmaceutical agents and/or the desired therapeuticand/or prophylactic effect to be achieved. In general, it is expectedthat the additional pharmaceutical agents utilized in combination beutilized at levels that do not exceed the levels at which they areutilized individually. In some embodiments, the levels utilized incombination will be lower than those utilized individually.

Exemplary additional pharmaceutical agents include, but are not limitedto, anti-proliferative agents, anti-cancer agents, anti-diabetic agents,anti-inflammatory agents, immunosuppressant agents, and a pain-relievingagent. Pharmaceutical agents include small organic molecules such asdrug compounds (e.g., compounds approved by the U.S. Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins, and cells.

Also encompassed by the invention are kits (e.g., pharmaceutical packs).The inventive kits may be useful for treating a proliferative disease(e.g., cancer (e.g., leukemia, melanoma, multiple myeloma), benignneoplasm, angiogenesis, inflammatory disease, autoinflammatory disease,or autoimmune disease). The kits provided may comprise the Pt-BASPsdescribed herein, or a pharmaceutical composition thereof, and acontainer (e.g., a vial, ampule, bottle, syringe, and/or dispenserpackage, or other suitable container). In some embodiments, providedkits may optionally further include a second container comprising apharmaceutical excipient for dilution or suspension of an inventivepharmaceutical composition or compound. In some embodiments, theinventive pharmaceutical composition or compound provided in thecontainer and the second container are combined to form one unit dosageform.

Methods of Treatment and Uses

The present invention also provides methods of using the Pt-BASPsdescribed herein, or a pharmaceutical composition thereof, for thetreatment or prevention of a proliferative disease such as cancer (e.g.lung cancer, large bowel cancer, pancreas cancer, biliary tract cancer,or endometrial cancer), benign neoplasm, angiogenesis, inflammatorydisease, autoinflammatory disease, or autoimmune disease in a subject.

In some embodiments, the Pt-BASPs described herein, or a pharmaceuticalcomposition thereof are useful in treating a cancer. In someembodiments, the Pt-BASPs described herein, or a pharmaceuticalcomposition thereof, are useful to delay the onset of, slow theprogression of, or ameliorate the symptoms of cancer. In someembodiments, the Pt-BASPs described herein, or a pharmaceuticalcomposition thereof, are administered in combination with othercompounds, drugs, or therapeutics to treat cancer.

In some embodiments, the Pt-BASPs described herein, or a pharmaceuticalcomposition thereof are useful for treating a cancer including, but notlimited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, analcancer, angiosarcoma (e.g., lymphangiosarcoma,lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benignmonoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma),bladder cancer, breast cancer (e.g., adenocarcinoma of the breast,papillary carcinoma of the breast, mammary cancer, medullary carcinomaof the breast), brain cancer (e.g., meningioma; glioma, e.g.,astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer,carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma),choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g.,colon cancer, rectal cancer, colorectal adenocarcinoma), epithelialcarcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma,multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g.,uterine cancer, uterine sarcoma), esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarcinoma), Ewingsarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma),familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g.,stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head andneck cancer (e.g., head and neck squamous cell carcinoma, oral cancer(e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g.,laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer,oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such asacute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acutemyelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphoma suchas Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkinlymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma(DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., “Waldenstrim's macroglobulinemia”), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma), heavy chain disease (e.g., alphachain disease, gamma chain disease, mu chain disease), hemangioblastoma,inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidneycancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma),liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma),lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer(SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung),leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis),myelodysplastic syndrome (MDS), mesothelioma, myeloproliferativedisorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis(ET), agnogenic myeloid metaplasia (AMM), a.k.a. myelofibrosis (MF),chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML),chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)),neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreaticneuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovariancancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarianadenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g.,pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm(IPMN), islet cell tumors), penile cancer (e.g., Paget's disease of thepenis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT),prostate cancer (e.g., prostate adenocarcinoma), rectal cancer,rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamouscell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cellcarcinoma (BCC)), small bowel cancer (e.g., appendix cancer), softtissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma,malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma,fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat glandcarcinoma, synovioma, testicular cancer (e.g., seminoma, testicularembryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of thethyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer),urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's diseaseof the vulva).

In some embodiments, the Pt-BASPs described herein, or a pharmaceuticalcomposition thereof, are useful in treating lung cancer, head-and-neckcancer, esophagus cancer, stomach cancer, breast cancer, pancreascancer, liver cancer, kidney cancer, prostate caner, glioblastomas,metastatic melanomas, peritoneal or pleural mesotheliomas.

In some embodiments, the proliferative disease is a benign neoplasm. Alltypes of benign neoplasms disclosed herein or known in the art arecontemplated as being within the scope of the invention. In someembodiments, the proliferative disease is associated with angiogenesis.All types of angiogenesis disclosed herein or known in the art arecontemplated as being within the scope of the invention. In certainembodiments, the proliferative disease is an inflammatory disease. Alltypes of inflammatory diseases disclosed herein or known in the art arecontemplated as being within the scope of the invention. In certainembodiments, the inflammatory disease is rheumatoid arthritis. In someembodiments, the proliferative disease is an autoinflammatory disease.All types of autoinflammatory diseases disclosed herein or known in theart are contemplated as being within the scope of the invention. In someembodiments, the proliferative disease is an autoimmune disease. Alltypes of autoimmune diseases disclosed herein or known in the art arecontemplated as being within the scope of the invention.

In certain embodiments, the methods described herein includeadministering to a subject with an effective amount of the Pt-BASPsdescribed herein, or a pharmaceutical composition thereof. In certainembodiments, the methods described herein include implanting to asubject with an effective amount of the Pt-BASPs described herein, or apharmaceutical composition thereof.

In certain embodiments, the Pt-BASPs described herein, or apharmaceutical composition thereof, are administered in combination withone or more additional pharmaceutical agents described herein. Incertain embodiments, the additional pharmaceutical agent is ananti-cancer agent. Anti-cancer agents encompass biotherapeuticanti-cancer agents as well as chemotherapeutic agents. Exemplarybiotherapeutic anti-cancer agents include, but are not limited to,interferons, cytokines (e.g., tumor necrosis factor, interferon α,interferon γ), vaccines, hematopoietic growth factors, monoclonalserotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1,2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) andantibodies (e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab),ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR(tositumomab)). Exemplary chemotherapeutic agents include, but are notlimited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol),LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g.flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin(BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellinA (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide),platinum containing compounds (e.g. cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine,and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalentsuch as nanoparticle albumin-bound paclitaxel (ABRAXANE),docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin),polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex,CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxelbound to the erbB2-recognizing peptide EC-1), and glucose-conjugatedpaclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate,teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMPdehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin,and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea anddeferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine,doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosineanalogs (e.g. cytarabine (ara C), cytosine arabinoside, andfludarabine), purine analogs (e.g., mercaptopurine and Thioguanine),Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylationinhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g.1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.staurosporine), actinomycin (e.g. actinomycin D, dactinomycin),bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline(e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g. verapamil), Ca²⁺ ATPase inhibitors (e.g. thapsigargin),imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g.,axitinib (AGO13736), bosutinib (SKI-606), cediranib (RECENTIN™,AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®),gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib(TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272),nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®,SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474),vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab(AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab(VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib(NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumabozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765,AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523,PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/orXL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTORinhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus(RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235(Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502(Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)),oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed,cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,aminopterin, and hexamethyl melamine.

In certain embodiments, the subject being treated is a mammal. Incertain embodiments, the subject is a human. In certain embodiments, thesubject is a domesticated animal, such as a dog, cat, cow, pig, horse,sheep, or goat. In certain embodiments, the subject is a companionanimal such as a dog or cat. In certain embodiments, the subject is alivestock animal such as a cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a zoo animal. In another embodiment, thesubject is a research animal such as a rodent, dog, or non-humanprimate. In certain embodiments, the subject is a non-human transgenicanimal such as a transgenic mouse or transgenic pig.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

All reagents and solvents were purchased from Aldrich or VWR and used assupplied unless otherwise noted. Platinum complexes 1 and 2 (Hall et al.J. Biol. Inorg. Chem. 2003, 8, 726), ruthenium catalyst C-1 (cat.; Love,J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem. Int. Ed.2002, 41, 4035), N-(glycine)-cis-5-norbornene-exo-dicarboximide 5 (al)(Conrad, R. M.; Grubbs, R. H. Angew. Chem. Int. Ed. 2009, 48, 8328), andnorbornene-PEG MM (PEG-MM, 4) (Liu, J.; Burts, A. O.; Li, Y.;Zhukhovitskiy, A. V.; Ottaviani, M. F.; Turro, N. J.; Johnson, J. A. J.Am. Chem. Soc. 2012, 134, 16337), were prepared according to literatureprocedures. Degassed dichloromethane (DCM) and tetrahydrofuran (THF)were passed through solvent purification columns prior to use.

Liquid chromatography-mass spectrometry (LC/MS) and preparative HPLCwere performed on an Agilent 1260 LC system equipped with a ZorbaxSB-C₁₈ rapid resolution HT column and a Zorbax SB-C₁₈ semi-preparativecolumn. Solvent gradients consisted of mixtures of nano-pure water with0.1% acetic acid (AcOH) and HPLC-grade acetonitrile. Mass spectra wereobtained using an Agilent 6130 single quadrupole mass spectrometer.

Dynamic light scattering (DLS) measurements were made at roomtemperature using a Brookhaven ZetaPALS DLS instrument or a WyattTechnology DynaPro Titan DLS instrument. Samples were dissolved innanopure water at a concentration of ˜1 mg/mL. A fresh, clean,polystyrene cuvette was washed with compressed air to remove dust. Thesample solution was passed through a 0.4 μm TEFLON syringe filterdirectly into the cuvette; the cuvette was capped and placed in the DLSinstrument for particle sizing. At least 3 measurements were made persample and average hydrodynamic diameters were calculated by fitting theDLS correlation function using the CONTIN routine (ISDA software packagefrom Brookhaven instruments or Dynamics V6 software package from DynaProWyatt Technology).

¹H nuclear magnetic resonance (1H-NMR), ¹³C nuclear magnetic resonance(¹³C-NMR), and ¹⁹⁵Pt nuclear magnetic resonance (¹⁹⁵Pt-NMR) spectra wererecorded on Bruker AVANCE-400 NMR spectrometer, Mercury 300 MHzspectrometer, or INOVA 500 MHz spectrometer. Chemical shifts arereported in ppm and referenced to the CHCl₃ singlet at 7.26 ppm, DMSO at2.50 ppm or CH₂Cl₂ at 5.30 ppm. ¹³C-NMR spectra were referenced to thecenter line of the CDCl₃ triplet at 77.0 ppm, DMSO septet at 39.5 ppm orCD₂Cl₂ quintet at 54.0 ppm. ¹⁹⁵Pt-NMR spectra were referenced using anexternal K₂PtCl₆ in D₂O at −1628 ppm. Chemical shifts are expressed inparts per million (ppm), and splitting patterns are designated as s(singlet), d (doublet), t (triplet), m (multiplet) and br (broad).Coupling constants J are reported in Hertz (Hz). Nuclear magneticresonance (NMR) experiments were performed on either a Mercury 300 MHzspectrometer or an INOVA 500 MHz spectrometer. MESTRENOVA NMR 7.0.1software was used to analyze the NMR spectra.

Gel permeation chromatography (GPC) measurements were performed on anAgilent 1260 LC system with two Shodex KD-806M GPC columns in series at60° C. and a flow rate of 1 mL/min. N,N-Dimethyl formamide (DMF) with0.2 M LiBr was used as the eluent. A T-rEX refractive index detector(Wyatt) and a DAWN EOS 18 angle light scattering (MALS) detector (Wyatt)were used for polymer analysis.

High-resolution mass spectrometry (HRMS) was obtained using a BrukerDaltonics APEXIV 4.7 Tesla Fourier Transform Ion Cyclotron ResonanceMass Spectrometer (FT-ICR-MS).

TEM images were obtained at the MIT Center for Materials Science andEngineering on a JEOL 200CX TEM instrument equipped with a 1 k×1 k CCDcamera. The samples were prepared as follows: 5.0 μL of a 0.050 mg/mLsolution of 20×L (or 15×L) Pt-BASPs was deposited via pipet on top of acarbon film-coated 200-mesh copper grid (purchased from ElectronMicroscopy Sciences) placed on a piece of PARAFILM carbon-coated sideup. The sample was allowed to dry at room temperature and then ready forTEM imaging.

Photolysis experiments were performed using a Multiple Ray Lamp (UVP)fitted with an 8 W, long wave, filtered blacklight bulb (365 nm).

OVCAR3 cells (ATCC) were maintained in RPMI-1640 media supplemented with0.01 mg/mL recombinant human insulin (Gibco), 20% fetal bovine serum,and penicillin/streptomycin in a 5% CO₂ humidified atmosphere (37° C.).Assays and imaging were performed on cells passaged 12-24 h prior.Dose-response curves were fit using a four-parameter logistic regressionanalysis and statistical significance was assessed by two-tailed t-test(95% CI) for *P<0.01, **P<0.05, and ***P<0.001. Pt-BASPs describedherein were reconstituted in ultrapure water (18 M2) containing 5%D-glucose and stored at 4° C. in dark prior to use. Viability wasassessed by CELLTITER-GLO assay (Promega) following 72 h totalincubation time with MDLP-spiked OPTIMEM medium. 90 min after theintroduction of the Pt-BASPs, assay plates were exposed for 10 min witha portable UV lamp (UVP Inc; 2.0±0.3 mW/cm² at 365 nm) and returned tothe incubator. Confocal fluorescence measurements were performedfollowing incubation with 133 μM acridine orange (Sigma) and 66.6 μg/mLPt-BASP in complete basal medium. After 30 min, cell growth media werereplaced with 10 mM HEPES (pH 7.4) containing 10% FBS and imaging (1exposure min⁻¹) was performed using the 405, 488, and/or 561 nm laserlines of a Nikon 1AR ultra-fast spectral scanning confocal microscope(λ_(em): 525/50, 595/50 nm) fitted with a temperature-controlledenvironment chamber and 60× oil immersion objective.

Example 1 Preparation of XL3 Pt(IV) Cisplatin Prodrug

Synthesis of Norbornene Anhydride 3.

N-(glycine)-cis-5-norbornene-exo-dicarboximide 5 (760 mg, 3.4 mmol) andN,N′-Dicyclohexylcarbodiimide (DCC) (360 mg, 1.7 mmol) were dissolved inanhydrous DCM (60 mL) and the resulting solution was stirred at roomtemperature overnight. The reaction mixture was then filtered and thefiltrate was concentrated via rotary evaporator to give 3 as white solid(583 mg, 80% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.31 (t, J=1.8 Hz, 2H),4.38 (s, 2H), 3.35-3.31 (m, 2H), 2.78 (d, J=1.4 Hz, 2H), 1.65 (d, J=10.1Hz, 1H), 1.54 (dt, J=10.1, 1.4 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ176.6, 161.6, 138.0, 48.1, 45.4, 42.9, 39.9. IR (neat): 1701, 1709,1411, 1079 cm⁻¹. MS (ESI) m/z (M+Li)⁺ calculated for C₂₂H₂₀N₂O₇Li:431.1. observed: 431.1.

Synthesis of Cross-Linker XL3.

Norbornene anhydride 3 (550 mg, 1.3 mmol) and platinum complex 2 (100mg, 0.30 mmol) were dissolved in anhydrous DCM (10 mL), and theresulting solution was stirred at room temperature for 2 weeks. Thereaction mixture was then filtered, and the residue solid was washedwith DCM (20 mL×3). The solid was collected and dried in vacuo to giveXL3 (white solid, 199 mg, 90% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 6.50(s, br, 6H), 6.31 (s, 4H), 4.13 (s, 4H), 3.10 (s, 4H), 2.70 (s, 4H),1.66 (d, J=9.0 Hz, 2H), 1.32 (d, J=9.0 Hz, 2H). ¹³C NMR (101 MHz,DMSO-d₆) δ 176.8, 174.0, 137.8, 47.2, 44.6, 42.6. (NOTE: one peak forthe compound is buried under the solvent picks.) ¹⁹⁵Pt NMR (86 MHz,DMSO-d₆) δ 1234.3. IR (neat): 1712, 1682, 1246, 1178 cm⁻¹. MS (ESI) m/z(M+H)⁺ calculated for C₂₂H₂₇Cl₂N₄O₈Pt: 741.0837. observed: 741.0837.

Example 2 Preparation of Macromonomer DOX-MM

Two macromonomers CPT-MM and DOX-MM (FIG. 15A) were prepared. CPT-MM andDOX-MM are branched MMs (Burts, A. O.; Li, Y. J.; Zhukhovitskiy, A. V.;Patel, P. R.; Grubbs, R. H.; Ottaviani, M. F.; Turro, N. J.; Johnson, J.A. Macromolecules 2012, 45, 8310) that release unmodified CPT and DOX inresponse to acidic media (Chen, X.; McRae, S.; Parelkar, S.; Emrick, T.Bioconjugate Chem. 2009, 20, 2331) and long-wavelength UV light,respectively. Both MMs feature a 3 kDa poly(ethylene glycol) (PEG) chainthat confers water solubility and neutral surface charge to the finalPt-BASPs (Greenwald, R. B.; Choe, Y. H.; McGuire, J.; Conover, C. D.Adv. Drug Delivery Rev. 2003, 55, 217; Arvizo, R. R.; Miranda, O. R.;Moyano, D. F.; Walden, C. A.; Giri, K.; Bhattacharya, R.; Robertson, J.D.; Rotello, V. M.; Reid, J. M.; Mukherjee, P. PLoS One 2011, 6).

Synthesis of 5-(3-chloropropoxy)-2-nitrobenzaldehyde b2

Compound b2 may be prepared according to reported methods (see, e.g.,Gumbley, P.; Koylu, D.; Thomas, S. W. Macromolecules 2011, 44, 7956).1-Bromo-3-chloropropane (0.650 mL, 0.00658 moles) was added to asolution of 5-hydroxy-2-nitrobenzaldehyde (1.0 g, 0.00598 moles), andpotassium carbonate (1.66 g, 0.0120 moles) in anhydrous DMF (6 mL). Thesolution was stirred at 40° C. for 24 hours. The reaction was dilutedwith ethyl acetate (75 mL) and washed with saturated sodium bicarbonatesolution (75 mL), water (75 mL), and brine (75 mL). The organic layerwas dried with anhydrous magnesium sulfate, which was removed byfiltration. The filtrate was concentrated, and the resulting residue wassubject to silica gel chromatography using a gradient of 100% hexanes to50% ethyl acetate in hexanes. The fractions containing the product werecollected, and volatiles were removed by rotary evaporation. Theresulting residue was dried overnight to yield5-(3-chloropropoxy)-2-nitrobenzaldehyde as a bright-green yellow solid(yield 87%*). ¹H NMR (400 MHz, CD₂Cl₂) δ 10.42 (s, 1H), 8.15 (d, J=9.1Hz, 1H), 7.32 (d, J=2.9 Hz, 1H), 7.18 (dd, J=9.0, 2.9 Hz, 1H), 4.27 (t,J=5.9 Hz, 2H), 3.76 (t, J=6.3 Hz, 2H), 2.35-2.24 (m, 2H). ¹³C-NMR (100MHz, CD₂Cl₂) δ 189.05, 163.84, 135.04, 127.84, 119.16, 114.57, 66.28,41.74, 32.35 HRMS m/z: calculated for C₁₀H₁₀ClNO₄ [M+H]⁺, 244.0371.found, 244.0366.

*Observed extra peaks, but does not interfere with next step: ¹H NMR(400 MHz, CD₂Cl₂) δ 4.27 (t, J=5.9 Hz, 0.16), 3.62 (t, J=6.4 Hz, 0.15H),2.39-2.36 (m, 0.14H).

Synthesis of (5-(3-chloropropoxy)-2-nitrophenyl)methanol b3

Sodium borohydride (133 mg, 0.00351 moles) was added to5-(3-chloropropoxy)-2-nitrobenzaldehyde (570 mg, 0.00234 moles) inanhydrous methanol (12 mL) at 0° C. under nitrogen. The reaction wasstirred for 1.5 hours and then concentrated with a rotary evaporator.The mixture was diluted with ethyl acetate (75 mL) and washed with 30 mLeach of saturated sodium bicarbonate solution, water, and brine. Theorganic layer was dried with anhydrous magnesium sulfate, which wasremoved by filtration. The filtrate was concentrated, and the resultingresidue was subject to silica gel chromatography using a gradient of100% hexanes to 60% ethyl acetate in hexanes. The fractions containingthe product were collected and volatiles were removed by rotaryevaporation. The resulting residue was dried overnight to yield(5-(3-chloropropoxy)-2-nitrophenyl)methanol as a pale yellow solid(yield 69%*). ¹H NMR (400 MHz, CD₂Cl₂) δ 8.16 (d, J=9.1 Hz, 1H), 7.27(d, J=2.7 Hz, 1H), 6.92 (dd, J=9.1, 2.8 Hz, 1H), 4.98 (s, 2H), 4.24 (t,J=5.9 Hz, 2H), 3.77 (t, J=6.3 Hz, 2H), 2.28 (p**, J=6.1 Hz, 2H). ¹³C-NMR(100 MHz, CD₂Cl₂) δ 163.99, 141.21, 128.42, 114.95, 113.90, 65.80,63.24, 41.91, 32.52 HRMS m/z: calculated for C₁₀H₁₂ClNO₄ [M+H]⁺,246.0528. found, 246.0529.

*Observed extra NMR peaks, but does not interfere with next step: ¹H NMR(400 MHz, Methylene Chloride-d2) δ 3.63 (t, J=6.3 Hz, 0.14H), 2.39-2.31(m, 0.24H). ** Pseudo pentet.

Synthesis of (5-(3-azidopropoxy)-2-nitrophenyl)methanol b4

DMF (7.5 mL) was added to (5-(3-chloropropoxy)-2-nitrophenyl)methanol(635 mg, 0.00258 moles) and sodium azide (252 mg, 0.00387 moles) in aflask, and the resulting mixture was heated to 70° C. and stirredovernight. The reaction was diluted in ethyl acetate (100 mL) and washedtwice with water (75 mL each) and once with brine (75 mL). The organiclayer was dried with anhydrous magnesium sulfate, which was filteredout. The filtrate was concentrated on a rotary evaporator and dried invacuo overnight to yield (5-(3-azidopropoxy)-2-nitrophenyl)methanol as ayellow solid (yield 88%). H NMR (400 MHz, CD₂Cl₂) δ 8.16 (d, J=9.1 Hz,1H), 7.27 (d, J=2.8 Hz, 1H), 6.91 (dd, J=9.1, 2.8 Hz, 1H), 4.98 (s, 2H),4.18 (t, J=6.0 Hz, 2H), 3.53 (t, J=6.6 Hz, 2H), 2.12-2.06 (m, 2H).¹³C-NMR (100 MHz, CD₂Cl₂) δ 163.99, 141.22, 128.43, 114.97, 113.93,66.15, 63.26, 48.68, 29.13 HRMS m/z: calculated for C₁₀H₁₂N₄O₄ [M+H]⁺,253.0931. found, 253.0939.

Synthesis of compound b5

A previously reported reaction (Johnson, J. A.; Lu, Y. Y.; Burts, A. O.;Xia, Y.; Durrell, A. C.; Tirrell, D. A.; Grubbs, R. H. Macromolecules2010, 43, 10326) was modified. A solution of(5-(3-azidopropoxy)-2-nitrophenyl)methanol (250 mg, 0.00099 moles) andtriethylamine (0.21 mL, 0.0015 moles) in tetrahydrofuran (5 mL) wasadded dropwise to a flask containing 4-nitrophenyl chloroformate (423mg, 0.0021 moles) in tetrahydrofuran (15 mL) at 0° C. under nitrogen.The ice-bath was removed, and the reaction was left to stir for onehour. The mixture was concentrated on a rotary evaporator and purifiedby silica gel chromatography eluted with a gradient from 100% hexanes to100% ethyl acetate. The fractions containing the product wasconcentrated on a rotary evaporator and dried in vacuo overnight toyield b5 as a yellow solid (yield 65%*). ¹H NMR (400 MHz, CD₂Cl₂) δ8.31-8.25 (m, 2H), 8.23 (d, J=9.2 Hz, 1H), 7.49-7.40 (m, 2H), 7.20 (d,J=2.7 Hz, 1H), 6.99 (dd, J=9.2, 2.8 Hz, 1H), 5.72 (s, 2H), 4.19 (t,J=6.0 Hz, 2H), 3.55 (t, J=6.5 Hz, 2H), 2.16-2.05 (m, 2H). *Observedimpurity peaks, but does not interfere with next step: ¹H NMR (400 MHz,CD₂Cl₂) δ 8.12-8.08 (m), 6.92-6.88 (m). ¹³C-NMR (100 MHz, CD₂Cl₂) δ163.88, 156.02, 152.65, 146.13, 140.66, 134.37, 128.73, 126.5, 125.81,122.35, 116.1, 115.11, 114.15, 68.12, 66.33, 48.58, 29.02 HRMS m/z:calculated for C₁₇H₁₅N₅O₈ [M+NH₄]⁺, 435.1259. found, 435.1251.

Synthesis of compound DOX-N₃

Doxorubicin hydrochloride (70.6 mg, 0.000122 moles) was dissolved DMF(1.5 mL), followed by addition of N,N-diisopropylethylamine (DIPEA)(0.021 mL, 0.000122 moles) and b5 (48 mg, 0.000116 moles). The solutionwas stirred at room temperature overnight, diluted with ethyl acetate(75 mL), and washed twice with water (50 mL each) and brine (50 mL). Theorganic layer was dried with anhydrous magnesium sulfate, which wasremoved by filtration. The filtrate was concentrated, and the residuewas subject to silica gel chromatography using a gradient of 100%dichloromethane to 10% methanol in dichloromethane. The fractionscontaining the product were collected, and volatiles were removed byrotary evaporation. The resulting residue was dried overnight to yieldDOX-N₃ as a red solid (yield 92%*). ¹H NMR (400 MHz, CD₂Cl₂) δ 13.94 (s,1H), 13.10 (s, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.91 (dd, J=7.7, 1.1 Hz,2H), 7.74 (t, J=8.1 Hz, 1H), 7.35 (dd, J=8.5, 1.1 Hz, 1H), 7.03-6.97 (m,1H), 6.86-6.81 (m, 1H), 5.54 (d, J=8.6 Hz, 1H), 5.51-5.47 (m, 1H), 5.40(dd, 24.6, 15.7, 1H), 5.24-5.19 (m, 1H), 4.74 (s, 2H), 4.60 (s, 1H),4.19-4.11 (m, 1H), 4.09 (t, J=6.0 Hz, 2H) 3.99 (s, 3H), 3.89-3.82 (m,1H), 3.68 (s, 1H), 3.48 (t, J=6.5 Hz, 2H), 3.22-3.12 (m, 1H), 2.94-2.87(m, 1H), 2.50 (s, 1H), 2.34 (d, J=14.7 Hz, 1H), 2.13 (dd, J=14.6, 4.1Hz, 1H), 2.02 (p**, J=6.3 Hz, 2H), 1.91-1.80 (m, 2H), 1.29 (d, J=6.5 Hz,3H). ¹³C-NMR (100 MHz, CD₂Cl₂) δ 214.52, 187.20, 163.64, 161.60, 156.56,155.90, 155.49, 140.54, 136.24, 135.77, 134.17, 133.96, 128.32, 120.00,119.21, 114.20, 113.48, 112.02, 111.87, 101.11, 77.18, 69.96, 67.96,66.08, 66.03, 63.99, 57.03, 48.57, 47.48, 36.09, 34.40, 30.61, 28.97,17.15 HRMS m/z: calculated for C₃₈H₃₉N₅O₁₆ [M+Na]⁺, 844.2284. found,844.2271. *Observed DMF, but does not interfere with the next step: ¹HNMR (400 MHz, CD₂Cl₂) δ 7.96 (s), 2.91 (s), 2.82 (s); ¹³C-NMR (100 MHz,CD₂Cl₂) δ 162.89, 36.79, 31.61. **Pseudo-pentet.

Synthesis of DOX-MM

To a solution of DOX-N₃ (49 mg, 0.060 mmol) and PEG-Alkyne-MM (300 mg,0.060 mmol) in 10 ml DCM was added CuOAc (0.6 mg, 4.8 μmmol) under N₂.The reaction was allowed to stir at room temperature and monitored byLC-MS until the complete consumption of PEG-Alkyne-MM. Then the solventwas removed under vacuum, and the residue was purified by HPLC elutedwith water (containing 0.1% acetic acid) and acetonitrile. The desiredDOX-MM was obtained as light yellow powder (174 mg, 70% yield). HRMS(MALDI): m/z ((M+Li)⁺ calculated for C₁₉₄H₃₃₆N₈O₈₇Li: 4177.23. observed:4176.73; m/z (M+MeOH+H)⁺ calculated for C₁₉₅H₃₄₁N₈O₈₈: 4203.25.observed: 4201.77. An ¹H NMR spectrum is shown in FIG. 25.

Example 3 Preparation of Macromonomer CPT-MM Synthesis of c2

A THF (35 mL) solution of the silyl ether c1 (Zhou, H.; Woo, J.; Cok, A.M.; Wang, M.; Olsen, B. D.; Johnson, J. A. Proc. Natl. Acad. Sci. USA2012) (3.5 g, 10.5 mmol) and tetra-n-butylammonium fluoride (TBAF) (5.5g, 21 mmol) was allowed to stir under N₂ at room temperature overnight.Then the reaction mixture was concentrated under vacuum, and the residuewas purified by flash chromatography eluted with hexanes and ethylacetate to give c2 (colorless oil, 2.3 g, 99% yield). The analytic datawere comparable to previously reported data (Sanders, B. C.; Friscourt,F.; Ledin, P. A.; Mbua, N. E.; Arumugam, S.; Guo, J.; Boltje, T. J.;Popik, V. V.; Boons, G.- J. J. Am. Chem. Soc. 2010, 133, 949).

Synthesis of c3

To a solution of c2 (1.1 g, 5.0 mmol) in acetone (55 mL) at 0° C. wasadded a solution of CrO₃ (1.5 g, 15 mmol) in 1.5 M H₂SO₄ in water (31mL) dropwise by an additional funnel. After addition, the reaction wasallowed to stir at room temperature overnight. The reaction was thenquenched by addition of isopropanol (30 mL) and concentrated undervacuum. The aqueous residue was extracted by DCM (50 mL×4). The organiclayers were combined, dried over Na₂SO₄, and concentrated under vacuum.The residue was purified by silica flash chromatography eluted withhexanes and ethyl acetate to give a colorless oil (1.2 g, 99% yield).The analytic data were comparable to previously reported data (Khiar,N.; Leal, M. P.; Baati, R.; Ruhlmann, C.; Mioskowski, C.; Schultz, P.;Fernandez, I. Chem. Commun. 2009, 4121).

Synthesis of CPT-N₃

The mixture of CPT (64 mg, 0.18 mmol), c3 (86 mg, 0.37 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl,71 mg, 0.37 mmol), and 4-dimethylaminopyridine (DMAP, 45 mg, 0.37 mmol)in DCM (10 mL) was allowed to stir under N₂ at room temperatureovernight. The reaction was then concentrated under vacuum, and theresidue was purified by flash chromatography eluted with 5% MeOH in DCMto give yellow solid (81 mg, 78% yield). ¹H NMR (400 MHz, Chloroform-d)δ 8.40 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.84(dd, J=8.0, 6.9, 1H), 7.68 (dd, J=8.4, 6.9, 1H), 7.21 (s, 1H), 5.70 (d,J=17.2 Hz, 1H), 5.42 (d, J=17.2 Hz, 1H), 5.29 (s, 2H), 4.36 (d, J=5.5Hz, 1H), 3.78-3.62 (m, 10H), 3.36 (t, J=7.5 Hz, 2H), 2.35-2.11 (m, 2H),0.98 (t, J=7.5 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 169.5, 167.1, 157.1,152.1, 148.7, 146.3, 145.2, 131.1, 130.5, 129.4, 128.3, 128.1, 128.0,127.9, 120.1, 95.7, 76.2, 70.9, 70.5, 70.5, 70.4, 69.8, 68.0, 67.0,50.5, 49.8, 31.6, 7.4. MS (ESI) m/z (M+Li)⁺ calculated for C₂₈H₂₉N₅O₈Li:564.2089. observed: 564.2098.

Synthesis of CPT-MM

To a solution of CPT-N₃ (50 mg, 0.089 mmol) and PEG-Alkyne-MM (300 mg,0.089 mmol) in 10 ml DCM, was added CuOAc (0.6 mg, 4.8 mmol) under N₂.The reaction was allowed to stir at room temperature and monitored byLC-MS until the complete consumption of PEG-Alkyne-MM. Then the solventwas removed under vacuum and the residue was purified by HPLC elutedwith water (containing 0.1% acetic acid) and acetonitrile. The desiredCPT-MM was obtained as light yellow powder (140 mg, 40% yield). HRMS(MALDI) m/z ((M+H₂O+Li)⁺ calculated for C₁₈₄H₃₂₈N₈O₈₀Li: 3939.52.observed: 3938.51; (M+Li)⁺ calculated for C₁₈₄H₃₂₆N₈O₇₉Li: 3919.19.observed: 3919.69. An ¹H NMR spectrum is shown in FIG. 26.

Example 4 Pt-BASP Formation Via ROMP

Pt-BASP syntheses were performed in a glovebox under an N₂ atmospherethough similar results may be expected under ambient conditions. Theweight content of all the drugs (CPT, DOX, and cisplatin) included in aPt-BASP (e.g., polymer P1, P2a, P2b, or P3) are 3.7% for polymer P1,5.5% for polymer P2b, 6.5% for polymer P2a, and 8.2% for polymer P3,compared to the total weight of the Pt-BASP.

Synthesis of P1

Macromonomer (MM) 4 (PEG-MM) was added to a 4 mL vial containing a stirbar. N equivalents of XL3 were added to a separate 2 mL vial containingstir bars. DCM was added to the vial with MM 4 followed by a freshlyprepared solution of catalyst C-1 (cat.) in DCM (2 mg cat./mL DCM,amount added to give desired MM 4:C-1 (m:1)) such that the totalconcentration of MM 4 was 0.05 M. After 10 minutes of stirring at 25°C., aliquots of the polymerization mixture were transferred to the vialscontaining XL3. The resulting mixtures were stirred at 25° C. for 6 hrs,at which point 1 drop of ethyl vinyl ether was added to quench thepolymerization. The DCM and excess ethyl vinyl ether were removed underreduced pressure.

In one set of experiments, PEG-MM (70.0 mg) was added to a 4 mL vialcontaining a stir bar. XL3 (6.4 mg) was added to a separate 4 mL vialcontaining a stir bar. THF (273 μL) was added to the vial with PEG-MMfollowed by a freshly prepared solution of catalyst cat. in THF (0.02mmol/mL, 152 μL) to give desired PEG-MM:cat. (mol:mol)=7. Note that thetotal concentration of PEG-MM was 0.05 M. After 20 minutes of stirringat 25° C., 406 μL of the polymerization mixture were transferred to thevial containing XL3. The resulting mixtures were stirred at 25° C. for 6hrs, at which point 1 drop of ethyl vinyl ether was added to quench thepolymerization. The THF and excess ethyl vinyl ether were removed underreduced pressure.

Synthesis of P2a

PEG-MM (48.4 mg) and CPT-MM (23.1 mg) were added to a 4 mL vialcontaining a stir bar. XL3 (6.4 mg) was added to a separate 4 mL vialcontaining a stir bar. THF (268 μL) was added to the vial with PEG-MMfollowed by a freshly prepared solution of catalyst cat. in THF (0.02mmol/mL, 149 μL) to give desired PEG-MM:cat. (mol:mol)=7. Note that thetotal concentration of CPT-MM and PEG-MM was 0.05 M. After 20 minutes ofstirring at 25° C., 406 μL of the polymerization mixture weretransferred to the vial containing XL3. The resulting mixtures werestirred at 25° C. for 6 hrs, at which point 1 drop of ethyl vinyl etherwas added to quench the polymerization. The THF and excess ethyl vinylether were removed under receded pressure.

Synthesis of P2b

PEG-MM (60.0 mg) and DOX-MM (9.7 mg) were added to a 4 mL vialcontaining a stir bar. XL3 (6.4 mg) was added to a separate 4 mL vialcontaining a stir bar. THF (265 μL) was added to the vial with PEG-MMfollowed by a freshly prepared solution of catalyst cat. in THF (0.02mmol/mL, 147 μL) to give desired PEG-MM:cat. (mol:mol)=7. Note that thetotal concentration of DOX-MM and PEG-MM was 0.05 M. After 20 minutes ofstirring at 25° C., 397 μL of the polymerization mixture weretransferred to the vial containing XL3. The resulting mixtures werestirred at 25° C. for 6 hrs, at which point 1 drop of ethyl vinyl etherwas added to quench the polymerization. The THF and excess ethyl vinylether were removed under reduced pressure.

Synthesis of P3

PEG-MM (38.8 mg), CPT-MM (22.3 mg), and DOX-MM (9.4 mg) were added to a4 mL vial containing a stir bar. XL3 (6.4 mg) was added to a separate 4mL vial containing a stir bar. THF (258 μL) was added to the vial withPEG-MM followed by a freshly prepared solution of catalyst cat. in THF(0.02 mmol/mL, 144 μL) to give desired PEG-MM:cat. (mol:mol)=7. Notethat the total concentration of CPT-MM, DOX-MM, and PEG-MM was 0.05 M.After 20 minutes of stirring at 25° C., 382 μL of the polymerizationmixture were transferred to the vial containing XL3. The resultingmixtures were stirred at 25° C. for 6 hrs, at which point 1 drop ofethyl vinyl ether was added to quench the polymerization. The THF andexcess ethyl vinyl ether were removed under reduced pressure.

Example 5 Characterization of Polymers P1, P2a, P2b, and P3

Upon completion of the brush-first ROMP reactions, the crude reactionmixtures were analyzed by gel permeation chromatography (FIG. 16). Inall cases, the conversion of MM to Pt-BASP was >90%.

Dynamic light scattering (DLS) revealed hydrodynamic diameters (D_(H))from 122-191 nm for the Pt-BASPs (Table 2 and FIG. 17). These values aresuitable for passive tumor targeting via the EPR effect (Matsumura, Y.;Maeda, H. Cancer Res. 1986, 46, 6387): they are larger than the ca. 6-8nm renal clearance threshold (Petros, R. A.; DeSimone, J. M. Nat. Rev.Drug Discovery 2010, 9, 615) and smaller than the 200-250 nm splenicclearance cutoff (Moghimi, S. M.; Hunter, A. C.; Murray, J. C.Pharmacological Reviews 2001, 53, 283).

Transmission electron microscopy (TEM) images of unstained Pt-BASPsshowed concentric dark and light regions (FIGS. 18 and 19). Theseresults can be attributed to the dense cisplatin core and PEG corona,respectively. The average diameters of the Pt-BASP as measured by TEM(D_(TEM)) in the dry state are provided in Table 2. CryoTEM images ofthe Pt-BASPs in aqueous solution (FIG. 20) show particle diameters thatagree well with the DLS data.

TABLE 2 Exemplary characterization data of exemplary Pt-BASPs: polymersP1, P2a, P2b, and P3 sample drug equiv. equiv. equiv. equiv. D_(TEM)^(a)/ D_(H) ^(b)/ name combination PEG-MM XL3 CPT-MM DOX-MM nm nm P1cisplatin only 7.00 3.00 0 0 125(15) 122(7) P2a cisplatin & CPT 4.933.00 2.07 0 114(20) 178(6) P2b cisplatin & DOX 6.17 3.00 0 0.831 110(19)191(7) P3 cisplatin & CPT & DOX 4.09 3.00 2.07 0.831 103(21)  180(10)Diameters as measured by transmission electron microscopy (TEM, D_(TEM))and dynamic light scattering (DLS, D_(H)). ^(a)TEM data were obtainedfrom dilute aqueous solutions cast onto a TEM grid, dried, and imagedwithout staining. Particle sizes were measured using IMAGEJ software.Values in parenthesis correspond to the standard deviation for at leastten particles. ^(b)D_(H) values were measure using 0.1 mg Pt-BASP/mL 5%glucose solutions. DLS correlation functions were fit using the CONTINalgorithm. Values in parentheses correspond to the standard deviationfor three particle measurements.

TABLE 3 Exemplary characterization data of exemplary Pt-BASPs: polymersP1, P2a, P2b, and P3 Sample M_(w)/kDa^(a)

% P1^(c) % DOX^(d) % CPT^(e) P1 142 1.2 3.7 NA NA P2a 182 1.4 3.6 NA 2.9P2b 103 1.7 3.7 1.8 NA P3 144 1.5 3.6 1.8 2.8 ^(a)Weight-averagemolecular weight (M_(w)) from GPC-MALLS. ^(b)Dispersity index(M_(w)/M_(n)). ^(c)Percent cisplatin by weight. ^(d)Percent DOX byweight. ^(e)Percent CPT by weight.

Example 6 In Vitro Platinum Release

In Phosphate Buffered Saline (PBS).

Drug release from Pt-BASPs was investigated using the dialysis method.The Pt-BASP sample m5N5 was dispersed in PBS with particle concentrationof 5 mg/mL. A 1 mL aliquot of the particle dispersion was transferredinto a dialysis membrane tubing with molecular weight cutoff of 10000 Daand dialyzed against 99 mL of PBS in a 37° C. water bath at a shakingspeed of 80 rpm. At predetermined time points, aliquots of 5 mL weretaken and added 150 μL 70% HNO₃ for the determination of platinumcontent by inductively coupled plasma atomic emission spectroscopy(ICP-AES) analysis.

In Phosphate Buffered Saline (PBS) Containing Glutathione (GSH).

The same procedure was performed as in PBS except that a solution of GSHin PBS (10 mM) was used instead of PBS.

Example 7 In Vitro Cellular Cytotoxicity Assays

Cell Culture.

Human Hela cell line was cultured at 37° C. under a humidifiedatmosphere of 5% CO2. The cells were grown in the final medium (FMEM)consist of 89% Eagle's minimum essential medium (EMEM, ATCC, 30-2003),10% fetal bovine serum (Gibco, 10437028) and 1% antibiotics (100 U/mLpenicillin and 100 μg/mL streptomycin, Gibco, 105140122). The cells werecontinuously maintained in the culture medium and subcultured every 3-4days.

Drug Treatment and Cell Viability Assay.

Hela cells were seeded at 10,000 cells/well in a 96-well plate andallowed to attach for 20 h before drug treatment. Prior to drugexposure, the culture medium was removed. Then, fresh media with drugconcentrations ranging from 0 to 400 μM (based on dry weight of polymerdissolved in FMEM) were added to the appropriate wells. The cells weresubsequently incubated in a cell culture incubator for 48 h. The mediumwas removed before fresh drug-free medium was added to each well. Thecells were incubated for another 24 h before analysis by the MTT cellproliferation assay (ATCC, 30-1010K). Cells were incubated with freshmedium containing MTT reagent for 4 h at 37° C. DMSO was added tosolubilize the purple formazan crystals formed by proliferating cells.Absorbance at 550 nm was measured on a Safire II (Tecan) plate reader.Data were fit to a sigmoidal function to determine the half-maximuminhibitory concentration (IC50).

Results.

Exemplary results of the cytotoxicity of polymers P1, P2a, P2b, and P3using OVCAR3 human ovarian cancer cells are shown in FIG. 21A. OCVAR3 isan established model cell line derived from a patient withplatinum-refractory (Godwin, A. K.; Meister, A.; Odwyer, P. J.; Huang,C. S.; Hamilton, T. C.; Anderson, M. E. Proc. Natl. Acad. Sci. U.S.A.1992, 89, 3070) disease that exhibits genotypic similarity with thehigh-grade serous subtype (Domcke, S.; Sinha, R.; Levine, D. A.; Sander,C.; Schultz, N. Nature Communications 2013, 4, 2126). Given thewidespread clinical use of anthracyclines and topoisomerase I inhibitorsin second-line therapies for recurrent ovarian carcinoma, OVCAR3 is asuitable model for BASP combination chemotherapy (Huinink, W. T. B.;Gore, M.; Carmichael, J.; Gordon, A.; Malfetano, J.; Hudson, I.; Broom,C.; Scarabelli, C.; Davidson, N.; Spanczynski, M.; Bolis, G.; Malmstrom,H.; Coleman, R.; Fields, S. C.; Heron, J. F. Journal of ClinicalOncology 1997, 15, 2183; Yap, T. A.; Carden, C. P.; Kaye, S. B. Nat.Rev. Cancer 2009, 9, 167). Exposure of OVCAR3 cells to 365 nm UV lightfor 10 min (0+hv) induced no observable toxicity. A non-agent-loadedBASP, P0 (FIG. 27; Liu, J.; Burts, A. O.; Li, Y.; Zhukhovitskiy, A. V.;Ottaviani, M. F.; Turro, N. J.; Johnson, J. A. J. Am. Chem. Soc. 2012,134, 16337), displayed toxicity only at very high concentrations (>650μg/mL) in the presence and absence of UV light (FIG. 22). Amongst theagent-loaded (e.g., drug-loaded) Pt-BASPs, polymer P1 had the largestIC₅₀ value: 192±46 μg/mL, 23±5 μM (FIG. 21A).

Polymer P2a showed a much lower IC₅₀: 44±15 μg/mL, 8±2 μM (FIG. 21A).Polymer P2b had an IC₅₀ of 217±23 μg/mL (32±3 μM) in the absence ofirradiation, which is not significantly different from polymer P1;exposure to UV for 20 min led to a 2.3±0.3-fold decreased IC₅₀ to 93±11μg/mL (14±1 μM) (FIG. 21A). No significant decrease in viability wasobserved following photo-exposure of polymers P1 and P2a (P=0.078 and0.018, respectively). These results suggest that therapeutically activecisplatin and CPT are released from these Pt-BASPs without an externaltrigger; DOX release is only significant upon irradiation.

When cells were treated with polymer P3 without UV irradiation, the IC₅₀was 42±6 μg/mL (9.2±0.8 μM) (FIG. 21A). This result can be rationalizedvia extrapolation of the results for polymers P1, P2a, and P2b: in theabsence of light, polymer P3 only released CPT and cisplatin, i.e., itbehaved similarly to P2a (P=0.81). After UV irradiation for 10 min, theIC₅₀ for P3 dropped 2.3±0.4-fold to 18±2 μg/mL (4.0±0.3 μM total drug);the 3-drug-loaded Pt-BASP (e.g., polymer P3) outperformed the 1- and2-drug loaded Pt-BASPs (e.g., polymers P1, P2a, and P2b).

Example 8 Cellular Internalization Assays

To examine cellular internalization of Pt-BASPs, a series of confocalfluorescence imaging experiments were conducted on live OCVAR3 cellsusing the inherent fluorescence of DOX. After 30 min of incubation withpolymer P2b in the dark, cells were briefly irradiated with 405 nm laserlight once per minute and imaged immediately afterwards for 25 min (DOXλ_(ex)/λ_(em)=561/595 nm). FIG. 23 shows images collected at varioustimes. Initially, punctate, extranuclear DOX fluorescence was observedto co-localize with acridine orange in the end/lysosomes (FIG. 23, 0min); photo-induced DOX release lead to rapid re-distribution offluorescence throughout the cytoplasm and nucleus and a 2.7-foldfluorescence intensity increase (FIG. 23, 25 min; FIG. 24).

To ensure that these results were due to DOX release, a controlexperiment was conducted wherein cells were pulsed with 561 nm lightrather than 405 nm. In this case, the particles remain trapped in theendosomes, and no increase in mean fluorescence intensity was observed.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those killed in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A platinum complex of Formula (I):

or a salt thereof, wherein: X₁ is F, Cl, Br, or I; X₂ is F, Cl, Br, orI; each instance of R^(N1) and R^(N2) is independently hydrogen,optionally substituted C₁₋₆ alkyl, or a nitrogen protecting group; ortwo R^(N1) are taken with the intervening atoms to form a heterocyclicring; or two R^(N2) are taken with the intervening atoms to form aheterocyclic ring; or R^(N1) and R^(N2) are taken with the interveningatoms to form a heterocyclic ring; and n is 1, 2, 3, 4, 5, or
 6. 2. Aplatinum complex of claim 1, wherein the complex is of Formula (II):

or a salt thereof.
 3. A platinum complex of claim 1, wherein the complexis of Formula (II-a):

or a salt thereof.
 4. The platinum complex of claim 1, wherein n is 1,2, or
 3. 5-6. (canceled)
 7. A method of preparing a platinum complex ofclaim 1, the method comprising steps of: (a) oxidizing a compound ofFormula (s-1) with an oxidant

to give a compound of Formula (s-2):

wherein: X₁ is F, Cl, Br, or I; X₂ is F, Cl, Br, or I; each instance ofR^(N1) and R^(N2) is independently hydrogen, optionally substituted C₁₋₆alkyl, or a nitrogen protecting group; or two R^(N1) are taken with theintervening atoms to form a heterocyclic ring; or two R^(N2) are takenwith the intervening atoms to form a heterocyclic ring; or R^(N1) andR^(N2) are taken with the intervening atoms to form a heterocyclic ring;and n is 1, 2, 3, 4, 5, or 6; and (b) coupling the compound of Formula(s-2) with a compound of Formula (s-3):

to yield a platinum complex of Formula (I). 8-10. (canceled)
 11. Amacromonomer of Formula (III):

or a salt thereof, wherein: a is an integer from 1 to 10, inclusive; bis an integer from 1 to 5 inclusive; c is an integer from 30 to 100inclusive; e is 0, 1, 2, 3, or 4; L is —O—, —S—, —NR^(La)—,—NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb), —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, —NR^(La)S(═O)₂—, or an optionally substituted C₁₋₁₀hydrocarbon chain, optionally wherein one or more carbon units of thehydrocarbon chain is replaced with —O—, —S—, —NR^(La)—, —NR^(La)C(═O)—,—C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—,—OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C═C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—, wherein each instance of R^(La) isindependently hydrogen, optionally substituted C₁₋₁₀ alkyl, or anitrogen protecting group, and wherein each occurrence of R^(Lb) isindependently selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(Lb) groups are joined to form anoptionally substituted carbocyclic or optionally substitutedheterocyclic ring, or R^(La) and R^(Lb) are joined to form an optionallysubstituted heterocyclic ring; and M is hydrogen or a therapeutic,diagnostic, or prophylactic agent.
 12. The macromonomer of claim 11,wherein L is of the formula:

wherein p is an integer from 1 to 10, inclusive; q is an integer from 1to 10, inclusive; each instance of R^(E) is halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted phenyl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, —OR^(A), N(R^(B))₂, —SR^(A), —C(═O)R^(A),—C(═O)OR^(A), —C(═O)SR^(A), —C(═O)N(R^(B))₂, —C(═O)N(R^(B))N(R^(B))₂,—OC(═O)R^(A), —OC(═O)N(R^(B))₂, —NR^(B)C(═O)R^(A),—NR^(B)C(═O)N(R^(B))₂, —NR^(B)C(═O)N(R^(B))N(R^(B))₂,—NR^(B)C(═O)OR^(A), —SC(═O)R^(A), —C(═NR^(B))R^(A), —C(═NNR^(B))R^(A),—C(═NOR^(A))R^(A), —C(═NR^(B))N(R^(B))₂, —NR^(B)C(═NR^(B))R^(B),—C(═S)R^(A), —C(═S)N(R^(B))₂, —NR^(B)C(═S)R^(A), —S(═O)R^(A),—OS(═O)₂R^(A), —SO₂R^(A), —NR^(B)SO₂R^(A), and —SO₂N(R^(B))₂; each R^(A)is independently selected from the group consisting of hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl; each R^(B) is independently selected from thegroup consisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(B)groups are taken together with their intervening atoms to form anoptionally substituted heterocyclic ring; each k is independently 0, 1,2, 3, 4, or 5; g is an integer from 1 to 10, inclusive; and h is aninteger from 1 to 10, inclusive.
 13. The macromonomer of claim 11,wherein the macromonomer is of Formula (III-a):


14. The macromonomer of claim 11, wherein the macromonomer is of Formula(III-b):


15. The macromonomer of claim 11, wherein the macromonomer is of Formula(III-c):


16. The macromonomer of claim 11, wherein the macromonomer is of Formula(III-d):


17. The macromonomer of claim 11, wherein M is of the formula:


18. The macromonomer of claim 1, wherein M is of the formula:


19. A polymer prepared by (a) reacting a macromonomer of claim 1, with ametathesis catalyst to form a polymerization mixture; and (b) mixing thepolymerization mixture from step (a) with a solution of a platinumcomplex of claim
 1. 20. The polymer of claim 19, wherein the amount ofthe macromonomer, platinum complex, and metathesis catalyst is of themolar ratio m:N:1, wherein m is an integer from 1 to 20, inclusive; andN is an integer from 1 to 20, inclusive.
 21. A polymer prepared by (a)reacting a first macromonomer of claim 11 with a second macromonomer ofclaim 11 in the presence of a metathesis catalyst to form apolymerization mixture; wherein M in the first macromonomer is differentfrom M in the second macromonomer; and (b) mixing the polymerizationmixture from step (a) with a solution of a platinum complex of claim 1.22-24. (canceled)
 25. A pharmaceutical composition comprising a polymerof claim 19 and a pharmaceutically acceptable excipient. 26-27.(canceled)
 28. A method of treating a proliferative disease comprisingadministering to a subject in need thereof a therapeutically effectiveamount of the polymer of claim
 19. 29. A method of treating aproliferative disease comprising implanting into to a subject in needthereof a therapeutically effective amount of the polymer of claim 19.30. (canceled)
 31. A method of conjugating polymer to aplatinum-containing therapeutic agent, the method comprising steps of:(a) oxidizing the platinum therapeutic agent with an oxidant to formplatinum hydroxide; (b) coupling the platinum hydroxide with a compoundof Formula (s-3)

to form a compound of Formula (I)

wherein X₁ is F, Cl, Br, or I; X₂ is F, Cl, Br, or I; each instance ofR^(N1) and R^(N2) is independently hydrogen, optionally substituted C₁₋₆alkyl, or a nitrogen protecting group; or two R^(N1) are taken with theintervening atoms to form a heterocyclic ring; or two R^(N2) are takenwith the intervening atoms to form a heterocyclic ring; or R^(N1) andR^(N2) are taken with the intervening atoms to form a heterocyclic ring;and n is 1, 2, 3, 4, 5, or 6; (c) reacting a macromonomer of Formula(III)

with a metathesis catalyst to form a polymerization mixture, wherein: ais an integer from 1 to 10, inclusive; b is an integer from 1 to 5inclusive; c is an integer from 30 to 100 inclusive; e is 0, 1, 2, 3, or4; L is —O—, —S—, —NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—,—C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—,—NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C≡C—,—OC(R^(Lb))₂—, —C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(La)—, —NR^(La)S(═O)₂—, or an optionallysubstituted C₁₋₁₀ hydrocarbon chain, optionally wherein one or morecarbon units of the hydrocarbon chain is replaced with —O—, —S—,—NR^(La), NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—,—C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—,trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—,—C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—,—OS(═O)₂—, —S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—, wherein each instance ofR^(La) is independently hydrogen, optionally substituted C₁₋₁₀ alkyl, ora nitrogen protecting group, and wherein each occurrence of R^(Lb) isindependently selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(Lb) groups are joined to form anoptionally substituted carbocyclic or optionally substitutedheterocyclic ring, or R^(La) and R^(Lb) are joined to form an optionallysubstituted heterocyclic ring; and M is hydrogen or a therapeutic,diagnostic, or prophylactic agent; and (d) mixing the compound ofFormula (I) from step (b) with the polymerization mixture from step (c)to yield a platinum-bound polymer. 32-36. (canceled)